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Pathogens 2022, 11, 1153. https://doi.org/10.3390/pathogens11101153 www.mdpi.com/journal/pathogens
Review
Resistance and Susceptibility Immune Factors at Play during
Mycobacterium tuberculosis Infection of Macrophages
Jan D. Simper 1,2, Esteban Perez 1,3, Larry S. Schlesinger 1,* and Abul K. Azad 1,*
1 Host-Pathogen Interaction Program, Texas Biomedical Research Institute, 8715 W. Military Drive,
San Antonio, TX 78227, USA
2 Department of Microbiology, Immunology and Molecular Genetics, UT Health Science Center San Antonio,
San Antonio, TX 78229, USA
3 Translational Sciences Program, UT Health San Antonio Graduate School of Biomedical Sciences,
San Antonio, TX 78229, USA
* Correspondence: lschlesinger@txbiomed.org (L.S.S.); aazad@txbiomed.org (A.K.A.);
Tel: +210-258-9578 (L.S.S.); +210-258-9467 (A.K.A.)
Abstract: Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M.tb), is responsi-
ble for >1.5 million deaths worldwide annually. Innate immune cells, especially macrophages, are
the first to encounter M.tb, and their response dictates the course of infection. During infection,
macrophages exert a variety of immune factors involved in either controlling or promoting the
growth of M.tb. Research on this topic has been performed in both in vitro and in vivo animal mod-
els with discrepant results in some cases based on the model of study. Herein, we review macro-
phage resistance and susceptibility immune factors, focusing primarily on recent advances in the
field. We include macrophage cellular pathways, bioeffector proteins and molecules, cytokines and
chemokines, associated microbiological factors and bacterial strains, and host genetic factors in in-
nate immune genes. Recent advances in mechanisms underlying macrophage resistance and sus-
ceptibility factors will aid in the successful development of host-directed therapeutics, a topic em-
phasized throughout this review.
Keywords: tuberculosis; macrophages; mouse model; innate immunity; host defense; host genetic
variation
1. Introduction
Mycobacterium tuberculosis (M.tb) is an intracellular pathogen that has been causing
disease in humans for thousands of years and continues to be among the most lethal in-
fectious diseases today. Tuberculosis (TB) infection is caused by the inhalation of airborne
droplets from individuals with active disease, although 90–95% of primary infections lead
to asymptomatic control rather than progression to active disease [1]. This suggests the
presence of innate immune factors that both respond to initial TB infection and reduce the
risk of latent TB reactivation. Central to regulating these immune factors and response to
M.tb are macrophages. Among the challenges that come with identifying such factors in
macrophages include differences between animal models and human data. For example,
the immune factor nitric oxide (NO) is critical for M.tb control in mice [2], but the early
control of M.tb growth in human macrophages was shown to be NO-independent [3]. In
this review, we will discuss similarities and differences between study models in each
section as appropriate. We will focus this review on recent advances in our understanding
of the innate immune factors that help control or promote M.tb infection by macrophages
(summarized in Table 1) and how these may help define new host-directed therapeutic
approaches. It is noteworthy that most of the work in this area is in in vitro tissue culture
macrophage models and cell lines with limited attention to alveolar macrophages (AMs)
Citation:
Simper, J.D.; Perez, E.;
Schlesinger, L.S.; Azad, A.K.
Resistance
and Susceptibility
Immune Factors at
Play during
Mycobacterium tuberculosis
Infection
of Macrophages.
Pathogens 2022, 11,
1153. https://doi.org/10.3390/
pathogens11101153
Academic
Editors: Delphi Chatterjee
and
Jordi B. Torrelles
Received:
26 August 2022
Accepted: 1 October 2022
Published:
6 October 2022
Publisher’s Note:
MDPI stays neu-
tral with regard to jurisdictional
claims in published maps and institu-
tional affiliations.
Copyright:
© 2022 by the authors. Li-
censee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and con-
diti
ons of the Creative Commons At-
tribution (CC BY) license (https://cre-
ativecommons.org/licenses/by/4.0/).
Pathogens 2022, 11, 1153 2 of 25
which are the unique, first macrophage type that is infected by M.tb and initiates patho-
genesis [4]. Aside from AMs, human blood monocyte-derived macrophages (MDMs) are
the current best alternative primary human macrophage type to study, with the benefit of
increased translation to human disease but with some differences in the expression of and
response to immunological factors [5]. Cell lines commonly used in TB research are THP-
1 and U937 cells, which are human monocytic cell lines isolated from leukemia patients
and which can be differentiated into macrophage-like cells [6]. These are more distant
models from human AMs but offer technical ease of use. Mouse cell lines include RAW
264.7 macrophages as perhaps the most commonly used model, although bone marrow-
derived macrophages (BMDMs) and macrophages isolated from lung homogenates are
also used. Finally, animal models include mice, rabbits, guinea pigs, zebrafish, and non-
human primates, each with varying susceptibility to M.tb infection and translatability to
human disease [7].
Table 1. Immune Factors Regulating M.tb Infection of Macrophages.
Innate factors
Host/Cell type
Biological effects during host-M.tb interaction
Reference
Cellular Pathways:
Mcl-1 Human MDMs
Treatment of macrophages with Mcl-1 antagonists re-
sulted in significantly decreased M.tb growth
[8]
Caspase-8 Mouse macrophages
Drives cell death of M.tb-infected macrophages, thereby
controlling infection [9]
Sirtuin 7 Mouse RAW 264.7
Helps control M.tb growth through NO-induced apopto-
sis
[10]
mTOR Mice
Increases autophagy and controls M.tb growth in infected
mice (lung homogenate)
[11]
Hydrogen sulfide Mouse RAW 264.7
Increases autophagy and controls M.tb growth in infected
cells
[12]
HIF-1
Human U937 monocytes
Increases autophagy and controls M.tb growth in infected
cells
[13]
DRAM2 Human MDMs
Binds to microtubule-associated proteins essential for the
initiation of autophagy and decreases M.tb growth
[14]
microRNA
miR-18a
Mouse RAW 264.7
Decreases LC3-II expression, required for autophago-
some formation, and promotes M.tb survival
[15]
CLEC4E
Mouse BMDMs
Enhances autophagy and decreases M.tb growth
[16]
TLR4
Mouse BMDMs
Enhances autophagy and decreases M.tb growth
[16]
Sirtuin 3 Mouse BMDMs
Involved in the expression of PPARα, an autophagy acti-
vator, and its KO macrophages show increased growth of
M.tb
[17]
P2X7 Mice
Detects ATP released during cellular stress or death path-
ways and activates the inflammasome, leading to de-
creased disease severity and M.tb CFUs in lung
[18]
P2RX7 Zebrafish
Potentiation through the drug clemastine improves my-
cobacterial infection control
[19]
HIF-1α Human MDMs
Presence in normoxic conditions decreases intracellular
M.tb growth and also decreases the release of TNFα and
IL-10.
[20]
Mice
Deficiency of HIF-1α increases lung bacterial burden in
infected mice
[21]
Mouse BMDMs
Deficiency of HIF-1α increases M.tb growth and impairs
the expression of glycolysis-related genes
[22]
Bioeffector Proteins and Molecules:
Pathogens 2022, 11, 1153 3 of 25
TLR2 Mouse BMDMs
A late, endosome-specific component of the TLR2 response
is inhibited by M.tb virulence factors PDIM and ESX-1 to im-
prove M.tb growth.
[23]
Mice
Critical for activation of Sirtuin 3 and protection against M.tb
in macrophages from lung and spleen
[24]
TLR9 Mouse BMDMs
Recognizes unmethylated CpG motifs in bacterial DNA and
plays role in the recognition and control of M.tb infection
[25]
IDO-1
Human and mouse
macrophages
Expression is upregulated by M.tb infection but is not essen-
tial for the control of M.tb growth in vitro.
[26]
Mice, Non-human
primates (NHP)
Expression correlates with the increase in mouse lung CFUs
of M.tb and treatment of rhesus macaques with an IDO-1 in-
hibitor decreases lung bacterial burden.
[27]
Human PBMCs,
MDMs
Represents one of the biochemical pathways in human mac-
rophages that prevents the efficient killing of M.tb in TB
granulomas
[28]
FAK Human THP-1
Overexpression leads to decreased M.tb survival, which is
due to increased ROS production
[29]
microRNA
miR-495
Human THP-1
Causes decreased M.tb survival through the increased pro-
duction of ROS and inhibition of SOD2
[30]
TARM-1 Mouse RAW 264.7
Knocking down of this receptor decreases the production of
ROS and increases the growth of M.tb H
37
R
v
[31]
FAO Mouse BMDMs
Inhibition of fatty acid oxidase leads to NADPH oxidase re-
cruitment and decreased M.tb growth [32]
CD157 Human MDMs
Macrophage treatment with soluble CD157 leads to de-
creased CFUs of M.tb, likely due to TLR2-dependent ROS
production
[33]
Liposomal gluta-
thione
Mice
An antioxidant that prevents damage to host immune cells
by ROS, but decreases lung CFUs of M.tb at the same time
[34]
Vitamin D Mice
Activated form induces the synthesis of LL-37, and admin-
istration of which in M.tb-infected mice leads to a reduction
in lung bacterial burden
[35,36]
Vitamin D + Phe-
nylbutyrate Human MDMs Inhibit the growth of MDR-TB strains [37]
PPARα Mouse BMDMs
Protective against infection, since KO mice show increased
M.tb growth compared to WT
[38]
PPARy Human MDMs
Permissive to infection, since knocking down of the gene sig-
nificantly decreases M.tb growth concomitant with an in-
crease in TNF
[39]
Other Cellular Factors:
Airway epithelial
cells (AECs)
Human alveolar epi-
thelial cells
Express PRRs, surfactant, and recruit neutrophils. Provide
protective host response against M.tb infection in the airway
environment which contains alveolar macrophages.
[40,41]
Lung-on-chip model
with mouse cells
Cells lacking surfactant allowed for the rapid growth of M.tb
further highlighting the importance of surfactant in bacterial
control in the alveolar environment which contains alveolar
macrophages
[42]
Cytokines and Chemokines:
TNF-α Zebrafish macro-
phages
Considered as a critical host resistance factor against TB but ex-
cess TNF confers TB susceptibility by increasing mitochondrial
ROS in infected macrophages.
[43]
Pathogens 2022, 11, 1153 4 of 25
Human PBMCs/ in
vitro granuloma
TNF-α antagonists differentially induce TGF-β1-dependent re-
suscitation of dormant M.tb
[44]
CD153 Human T cells
M.tb-specific CD4
+
T cells expressing CD153 is significantly re-
duced in patients with active TB
[45]
IL-6
Mice
KO mice are highly susceptible to M.tb infection
[46]
Mouse macrophages
M.tb-induced IL-6 inhibits macrophage response to IFN-γ
[47]
Human U937,
Mouse RAW 264.7
M.tb virulence factor, Rv3246c, enhances bacterial survival in
macrophages by inhibiting TNF-α and IL-6 production in an
NF-κB pathway-dependent manner
[48]
GM-CSF
Human MDMs,
Mouse AMs and
RAW 264.7
Enhances M.tb localization in acidic compartments,
resulting in
phagolysosomal fusion and bacterial clearance [49,50]
Human and Mouse
AMs
Human AMs after M.tb infection produce more GM-CSF, con-
ferring higher control of infection than mouse AMs
[51]
IL-1β Mice
Absence leads to M.tb outgrowth in the lungs and distant or-
gans and impaired granuloma formation containing fewer
macrophages
[52]
Mice,
Mouse macrophages
Absence of IL-1R signal leads to a dramatic defect in early con-
trol of M.tb infection in vivo and also in stimulated macro-
phages due to an absence of MyD88-dependent signaling
[53]
Human MDMs
Both gene and protein expression are decreased in MDMs from
active TB patients compared to LTBI subjects,
suggesting a role
for IL-1β in preventing TB reactivation
[54]
Type I IFN Mice (B6.Sst1 strain)
Uncontrolled production of type I IFN by mice increases their
susceptibility to M.tb
[55]
Mice,
Mouse BMDMs and
RAW 264.7
Type I IFN signaling mediates M.tb-induced macrophage
death. Its absence in combination with Rifampin treatment
leads to a significant reduction in CFUs in lungs and liver
[56]
Human
Patients with active TB have increased levels of type I IFN,
which correlates with disease severity
[57]
IFN-β Mouse BMDM
IFN-β signaling promotes protection against M.tb infection by
increasing the production of NO [58]
IFN-γ Human THP-1
Associated with limiting intracellular bacterial replication by
reducing hepcidin secretion in macrophages
[59]
Mice,
Mouse macrophages
Depletes intracellular histidine which is essential for M.tb sur-
vival both in vivo and ex vivo murine macrophages
[60]
IL-10 Human and mouse
macrophages
Production in macrophages is upregulated via the TLR2-ERK
pathway during M.tb infection. IL-10, through STAT3 induc-
tion, mediates anti-inflammatory response and diminishes an-
tibacterial activity
[61,62]
Human AMs,
MDMs and THP-1
Blocks phagosome maturation resulting in increased M.tb sur-
vival in macrophages
[63]
Human MDMs
Presence of alveolar lining fluid in infected cell culture releases
M.tb cell wall fragments resulting in the production of IL-10
which, coupled with STAT3 signaling, leads to macrophage-
mediated control and growth of M.tb
[64]
TGF-β
GranSim granuloma
model, NHP
Presence of TGF-β in TB granulomas inhibits the killing of in-
fected macrophages by cytotoxic T cells
[65]
Human PBMCs/ in
vitro granuloma
Adalimumab, an anti–TNF-α–targeting molecule, specifically
mediates TGF-β1-dependent resuscitation of dormant M.tb
[44]
Pathogens 2022, 11, 1153 5 of 25
IL-12
Human PBMCs,
macrophages
Promotes macrophage bactericidal activity, proliferation, and
cytosolic activity
[66]
Human/Mouse mac-
rophages and DCs
Mutations in IL-12 confer increased susceptibility to M.tb infec-
tion
[67]
Chemokines
Human immune
cells, macrophages
Recruit cells including macrophages into the M.tb-infected
lung which contributes to M.tb containment
[68]
CCL1, CCL3,
CXCL1, CXCL2,
CXCL10
Confirmed and Con-
trol TB subjects
Baseline levels of these plasma chemokines are significantly
higher in active TB patients compared to TB controls in chil-
dren
[69]
2. Brief overview of M.tb infection pathogenesis
M.tb is an airborne infection transmitted by the inhalation of droplets from active TB
patients. Bacteria in the droplets are deposited in the alveoli and encounter AMs, which
phagocytose the bacteria via different cell surface receptors [4,70,71]. Receptor-mediated
signaling and trafficking are critical in initiating the immune response, which either con-
trols or promotes TB infection and subsequently shapes the development of the adaptive
immune response [71,72]. Work continues to be performed on elucidating the intracellular
mechanisms underlying the differences in M.tb control by macrophages.
3. Cellular Pathways
Apoptosis, or programmed cell death, is an important host defense mechanism
against infection as it can promote pathogen clearance and resolution of inflammation
[73]. M.tb has evolved various strategies for inhibition of apoptosis, ranging from the in-
hibition of calcium influx, suppressing cell death pathways, or promoting the expression
of anti-apoptotic factors [74,75]. Our lab recently identified one such mechanism, in which
M.tb induces the expression of the peroxisome proliferator-activated receptor (PPAR)γ in
human MDMs, which in turn drives the expression of Mcl-1, a pro-survival member of
the Bcl-2 family. Treatment with Mcl-1 antagonists resulted in significantly decreased M.tb
growth in MDMs [8]. Another study described the critical role of caspase-8 in driving the
cell death of M.tb-infected mouse macrophages and the control of infection in mice by
enhancing apoptosis through the use of specific treatments [9]. Sirtuin 7 was another fac-
tor described to help control M.tb growth through NO-induced apoptosis in RAW 264.7
cells [10]. There has also been an increasing interest in studying the function of different
microRNAs in the context of programmed cell death [76–80]. Other microbiological and
host factors have also been described to attenuate the inflammatory response by inhibiting
apoptosis [81,82]. Overall, there is strong evidence that apoptosis is an important process
for M.tb control, and promoting the activity of this pathway as a viable host-directed ther-
apeutic approach is worth further investigation.
Autophagy is an evolutionarily conserved process in eukaryotic cells in which intra-
cellular components are transported to lysosomes for degradation and recycling. It is a
core process for the maintenance of cellular and organismal homeostasis [83]. There is
evidence that autophagy is an important process to control TB infection, and host-directed
therapies to promote autophagy have become more popular [84]. Recent advancements
include targeting the mammalian target of rapamycin (mTOR) signaling in mice [11], hy-
drogen sulfide in mouse RAW 264.7 macrophages [12], or hypoxia-inducible factor 1 (HIF-
1) in human U937 monocytes [13] to increase autophagy and the control of M.tb growth
in infected cells. It was also shown that the upregulation of DNA damage-regulated au-
tophagy modulator 2 (DRAM2), which is thought to play a role in the initiation of autoph-
agy, leads to decreased M.tb growth in human MDMs [14]. The upregulation of the mi-
croRNA miR-18a decreased LC3-II expression, a marker of autophagosome formation, in
RAW 264.7 cells, and promoted M.tb survival [15]. Our collaborative studies have also
shown that agonists of the C-type lectin receptor CLEC4E and Toll-like receptor TLR4
Pathogens 2022, 11, 1153 6 of 25
enhance autophagy and decrease M.tb growth in mouse bone marrow-derived macro-
phages (BMDMs) and lungs [16]. Finally, sirtuin 3 (SIRT3), an NAD+ dependent deacety-
lase, was shown to be important for the expression of PPARα, an activator of autophagy
in mouse BMDMs, and M.tb grew significantly more in SIRT3-/- BMDMs [17]. The induc-
tion of autophagy continues to show promise as an avenue for host-directed therapies
against TB infection.
An inflammasome is a group of intracellular protein complexes that are critical in the
innate immune system to respond to infection by activating caspase-1 to cleave pro-IL-
1β/IL-18 which then go on to trigger downstream inflammatory pathways [85]. Multiple
proteins can induce the formation of an inflammasome, such as NLRP3, AIM2, NLRC4,
or NLRP1, although NLRP3 is perhaps the most characterized. Triggering the inflam-
masome by M.tb requires the ESX-1 type VII secretion system [86–89], and it has been
suggested that this is due to plasma membrane damage mediated by ESX-1 [90]. There are
conflicting reports of whether inflammasome induction is beneficial for the control of M.tb
or whether too much of it can lead to worsened outcomes and an overly inflammatory
response. A recent study showed a decreased rate of the early growth of M.tb in infected
BMDMs from NLRP3-/- mice, as well as from WT mice administered with an NLRP3 in-
hibitor; however, the ability of different M.tb strains to induce inflammasome formation
was variable [91]. The inhibition of P2X7, a receptor that detects ATP released during cel-
lular stress or death pathways and activates the inflammasome, was associated with de-
creased disease severity in mice and CFUs per lung [18]. However, another study found
that P2RX7 potentiation through the drug clemastine improved M. marinum control in
zebrafish [19]. This highlights the importance of differences in disease models during the
study of TB, and more work is needed to elucidate the precise role of inflammasome sig-
naling during M.tb infection, especially in human macrophages.
M.tb infection of human AMs and MDMs has been described to induce a shift from
oxidative phosphorylation to aerobic glycolysis [92], and this shift has been found to be
required for the effective control of bacterial growth [93]. Aerobic glycolysis promotes the
activity of the transcription factor hypoxia-inducible factor 1α (HIF-1α), especially in IFN-
γ-activated macrophages, and macrophages lacking HIF-1α are defective in the IFN-γ-
mediated control of infection [93]. The treatment of human MDMs with a HIF-1α stabi-
lizer at normoxic conditions decreased intracellular M.tb growth, although it also de-
creased the release of TNFα and IL-10 [20]. Mice with HIF-1α-deficient myeloid cells dis-
played increased lung bacterial burden compared to WT mice 120 days post-infection and
when infected with hypervirulent M.tb, although this was not seen at lower dose infec-
tions [21]. A separate study found that BMDMs from mice lacking HIF-1α in their myeloid
cell lineage had increased M.tb growth, and the expression of glycolysis-related genes was
impaired by HIF-1α KO [22]. However, the chronic expression of HIF-1α can also lead to
unwanted pathology, and a mechanism was described by which IL-17 negatively regu-
lates HIF-1α to reduce lung bacterial burden and hypoxic granuloma formation in mice
[94]. As with many innate immune factors in TB, a balance must be maintained between
the immediate beneficial effects and harmful chronic complications.
4. Bioeffector Molecules
The first step in initiating an immune response to M.tb infection is the recognition of
pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors
(PRRs). The PRRs, known as Toll-Like Receptors (TLRs), play an important role in recog-
nizing M.tb ligands and polymorphisms in TLRs have been found to be associated with
increased TB susceptibility [95]. Various studies have identified Toll-like receptor 2
(TLR2), which recognizes lipomannan and lipoprotein from M.tb [96,97], and TLR9, which
recognizes unmethylated CpG motifs in bacterial DNA [25], as key TLRs for the recogni-
tion and control of M.tb infection in mouse BMDMs. TLR4 and TLR8 have also been stud-
ied in the context of TB infection [95]. It was recently discovered that the M.tb virulence
Pathogens 2022, 11, 1153 7 of 25
factors phthiocerol dimycocerosates (PDIM) and ESAT-6 secretion system 1 (ESX-1) in-
hibit a late endosome-specific component of the TLR2 response to improve M.tb growth
in mouse BMDMs [23]. TLR2 was also shown to be critical for the activation of SIRT3 and
protection against M.tb in mouse lungs and spleen [24].
Indoleamine 2,3-dioxygenase-1 (IDO-1) is the rate-limiting enzyme involved in tryp-
tophan metabolism to downstream metabolites such as kynurenine in host cells. It was
found that M.tb infection induced the upregulation of IDO-1 expression in both human
and murine macrophages, and infected macrophages produced an immunosuppressive
metabolite (kynurenine) that did not reduce M.tb growth in vitro [26]. IDO-1 expression
correlated with an increase in mouse lung CFUs and the treatment of rhesus macaques
with an IDO-1 inhibitor decreased lung bacterial burden [27]. IDO-1 likely represents one
of several biochemical pathways in macrophages that prevent the efficient killing of M.tb
in TB granulomas [28]. IDO-1, and by extension, the kynurenine/tryptophan ratio, has
therefore garnered interest as a possible biomarker for TB infection.
Reactive oxygen species (ROS) are highly reactive oxygen-containing molecules that
can destroy both pathogenic bacteria as well as host cell machinery. As an example,
NADPH oxidase catalyzes the transfer of electrons from NADPH to molecular oxygen to
form superoxide [98]. Multiple other ROSs, such as hydrogen peroxide, are then produced
and can react quickly with other molecules in their immediate cellular location. The over-
expression of focal adhesion kinase (FAK) in THP-1 macrophages led to decreased M.tb
survival, and this was due to increased ROS production [29]. The microRNA miR-495 was
shown to decrease the survival of H37Rv in THP-1 cells through the increased production
of ROS and the inhibition of SOD2 [30]. The knockdown of the receptor TARM-1 in RAW
264.7 cells decreased the production of ROS and increased the growth of M.tb H37Rv [31].
Additionally, the inhibition of fatty acid oxidase in mouse BMDMs led to NADPH oxidase
recruitment and decreased M.tb growth [32]. Interestingly, the depletion of platelets in
mice led to decreased lung CFUs by the increased production of ROSs [33]. The same
study found that the treatment of human MDMs with soluble CD157 led to the decreased
CFUs of M.tb and described a pathway by which CD157 participates in TLR2-dependent
ROS production [33]. However, although ROSs may be beneficial if they target pathogens,
they can also harm host cells and cause more inflammation. Protecting the host, therefore,
requires a potential therapy, and one study found that the supplementation of liposomal
glutathione, an antioxidant that prevents damage to immune cells by ROS, decreased lung
CFUs in mice [34]. Overall, there is support for the importance of ROS generation in com-
batting TB infection.
Cohort studies have shown that a deficiency in vitamin D is associated with an in-
creased risk of TB [99,100]. Activated vitamin D3 induces the synthesis of the cathelicidin
antimicrobial peptide LL-37, which enhances xenophagy [35], and the administration of
LL-37 in M.tb-infected mice led to a reduction in lung bacterial burden [36]. Different
strains of M.tb also required different concentrations of LL-37 to inhibit their growth [101].
However, randomized controlled clinical trials have not shown a benefit of vitamin D
supplementation in the prevention of disease [102,103], or that supplementation provided
additional benefit to patients already receiving antibiotics [104,105]. A recent study found
that vitamin D in conjunction with phenylbutyrate inhibited the growth of multi-drug
resistant tuberculosis (MDR-TB) strains in human macrophages [37]. More work is needed
to understand the precise role of vitamin D (potentially in combination with other micro-
nutrients) in controlling M.tb growth in macrophages.
Peroxisome proliferator-activated receptors (PPARs), of which there are three in hu-
mans (PPARα, PPARβ/δ, and PPARγ), are members of a ligand-binding nuclear receptor
family and regulate metabolic, differentiation, proliferation, and inflammatory pathways
in their roles as transcription factors [106]. PPARα was demonstrated to be protective
against infection since BMDMs from PPARα-/- mice had increased M.tb growth compared
to WT [38]. SIRT3 was also described to have anti-mycobacterial effects through PPARα
[17]. Work from our lab has shown that PPARγ knockdown in human MDMs significantly
Pathogens 2022, 11, 1153 8 of 25
decreases M.tb growth concomitant with an increase in TNF [39], suggesting differential
roles within the PPAR family members in M.tb control. As mentioned earlier, we also
showed that the inhibition of the PPARγ effector and anti-apoptotic protein Mcl-1 resulted
in greatly decreased M.tb growth in MDMs [8]. It was also found that the bacteriostatic
effect of vitamin B1 on M.tb growth in mouse BMDMs was PPARγ-dependent; treatment
with a PPARγ agonist alone increased M.tb growth [107]. Additionally, a model has been
suggested by which targeting PPARy leads to increased IL-1β, IL-12, and iNOS produc-
tion and decreased IL-10 production to protect against M.tb infection in a murine model
[108]. Overall, the evidence so far points to PPARα’s protective role and PPARγ’s permis-
sive role in the growth of M.tb in macrophages.
5. Other Cellular Factors
The alveolar lumen is composed of airway epithelial cells (AECs), which are subdi-
vided into alveolar type I cells and type II cells [109]. Type I cells are known for their
involvement in gas exchange [109] while type II cells are involved in the production and
recycling of lung surfactant [110]. AECs play an integral role in maintaining airway ho-
meostasis and have the capacity to respond to changes in the external and internal envi-
ronment via immunomodulatory secreted molecules [111]. Furthermore, these cells are
known to express PRRs and surfactant which are important in the recognition of M.tb by
lung cells [40]. An in vitro study showed that after exposure to M.tb or M.tb-infected mac-
rophages, AECs promote the recruitment of neutrophils, offering a strong indication that
they contribute to the protective host response against M.tb infection in the airway envi-
ronment [41]. Additionally, a study using a lung-on-a-chip model with mouse cells
showed that both alveolar epithelial cells and macrophages lacking surfactant allowed for
the rapid growth of M.tb, further highlighting the importance of surfactant in bacterial
control in an alveolar environment [42]. Finally, alveolar lining fluid, which bathes AMs,
contains enzymes called hydrolases that release M.tb cell envelope fragments extracellu-
larly which in turn improve the ability of macrophages to control M.tb growth by initiat-
ing a robust innate immune response [64].
6. Microbiological Factors
ManLAM: M.tb has a complex cell envelope containing predominantly unique gly-
colipids and lipoglycans that confer a survival advantage for bacteria and that vary in
strains of different lineages, potentially explaining differences in their virulence [112–114].
Among the most studied is mannose-capped lipoarabinomannan (ManLAM), a heteroge-
neous, amphipathic lipoglycan that serves as both an immunogen and virulence factor for
M.tb [115,116]. It is composed of a phosphatidyl-myo-inositol (PI) anchor, a carbohydrate
core, and various mannose-capping motifs [117]. The recognition of ManLAM in the lipid-
rich cell wall of M.tb by the macrophage mannose receptor (MR, CD206) leads to a path-
way of the intracellular survival of bacteria within the host by blocking phagosome fusion
with lysosomes [118,119]. Binding to MR also produces an anti-inflammatory response as
measured by the production of IL-10 and TGF-β while limiting the production of pro-
inflammatory cytokines such as TNF, IL-6, IL-1β, and IL-12 [120,121]. Additionally, Man-
LAM binding to MR enhances the expression of the nuclear receptor PPARγ and the sig-
nal transducer and activator of transcription (STAT)-5α [39]. An aptamer that inhibited
M.tb entry into murine macrophages by targeting ManLAM led to increased IL-1β and IL-
12 production but decreased IL-10 production [108]. More work needs to be performed
for elucidating the intracellular signaling pathways triggered by ManLAM and their po-
tential as therapeutic targets for TB infection.
ESAT-6/ESX-1: ESAT-6 secretion system 1 (ESX-1) is a type VII secretion system and
a major M.tb virulence factor, with host effects ranging from the induction of necrosis,
autophagy, NOD2 signaling, and type I interferon production [122]. Additionally, the per-
foration of phagosomes in macrophages is mediated by M.tb ESX-1 through ESAT-6 [123],
thereby enhancing M.tb virulence via the release of M.tb molecules into the cytosol [124]
Pathogens 2022, 11, 1153 9 of 25
or by the translocation of M.tb into the cytosol [123]. Cytosolic translocation was found to
be a feature of only virulent mycobacterial strains [123]. To further enhance virulence,
M.tb strain H37Rv suppresses the apoptosis of macrophages by acting on members of the
anti-apoptotic Bcl-2 family, especially Mcl-1 [8,125]. Additionally, this strain funnels cell
death down the pathway of the necrosis of infected neutrophils in an ESAT-6-dependent
manner, a process that promotes bacterial growth following uptake by macrophages [126].
Because of its strong virulence and potent antigenic properties, ESAT-6 is being used for
the development of a new preventive and therapeutic vaccine for TB [127].
7. Mycobacterial Strains
There are many adaptations that M.tb has evolved over the course of its history, and
the strains can differ from one another in their beneficial mutations. The M.tb Rv1096
strain was recently found to accelerate its growth in RAW 264.7 cells and dampen pro-
inflammatory cytokine production as well as NF-κB and MAPK signaling [128]. The M.tb
protein Rv0455c was shown to be a virulence factor as a Δrv0455c mutant had impaired
growth in lung and spleen homogenates due to decreased iron uptake [129]. Different
strains may induce different immune cell and cytokine responses, such as IL-22 being im-
portant for protective immunity against the hypervirulent HN878 strain but not against
the lesser virulent H37Rv strain [130]. In a study on the interplay between different M.tb
strains and races/ethnicities, strain CDC1551 elicited lower levels of IL-1, IL-6, IL-10, TNF-
α, and GM-CSF production from human MDMs and higher levels of IL-8, compared to
H37Rv and HN878 [131]. Factors that are not important for the control of one M.tb strain
may have a more important role for a different strain, such as having been recently shown
with CCR2-/- mice being more susceptible to HN878 compared to H37Rv [132]. Infection
with the M.tb Erdman strain led to a higher lung bacterial burden and a greater systemic
inflammation due to increased response to hypoxia compared to CDC1551 in a non-hu-
man primate model [133]. It is evident that different strains induce differential host re-
sponses mediated in large part by macrophages; therefore, the development of future
host-directed therapies will need to take these differences into account to achieve the most
success.
8. Other Microbiological Factors
Much work is being performed to identify important genes and factors for M.tb vir-
ulence and survival. The knockout of the Rv2617c gene in the CDC1551 strain reduced its
growth in mice and decreased oxidative stress resistance [134]. The M.tb PE_PGRS20 and
PE_PGRS47 proteins interact with the Ras-related protein Rab1A to prevent autophagy in
infected host cells and infection of THP-1 macrophages with deletion mutants showed
decreased growth [135]. The balance of micronutrients is important for M.tb survival. The
bacterial ATPase CtpB was found to be important for the regulation of copper levels and
the optimal growth of M.tb both in vitro and in the mouse model [136]. The ability of M.tb
to mutate and overcome the loss of the ESX-3 type VII secretion system, involved in iron
acquisition, and thus restore virulence, has also been described in the mouse model [137].
Interestingly, the aggregation of M.tb bacilli was described to cause earlier pro-inflamma-
tory gene activation and cell death compared to infection with a non-aggregated one or
multiple single bacilli in human MDMs [138]. Overall, the characterization of the micro-
biological factors important for the growth and survival of M.tb continues to shed new
light on the host-pathogen interactions and deepen our understanding of bacterial viru-
lence mechanisms.
9. Immune Factors: Cytokines
TNF-α: TNF-α is a pro-inflammatory cytokine important in controlling M.tb infec-
tion, and its production is primarily carried out by cells of the monocytic lineage, includ-
ing macrophages [139]. During M.tb infection, TNF-α is one of the earliest cytokines to be
Pathogens 2022, 11, 1153 10 of 25
produced. TNF-α signals through two trimeric membrane receptors: TNF receptors
1(TNF-R1) and (TNF-R2) [140] or by reverse signaling back into the membrane of TNF-
producing cells [141]. Consequently, TNF signaling can result in a diversity of biological
functions. Although TNF-α is considered to be a critical host resistance factor against TB,
a recent report [43] showed that excess TNF confers susceptibility by increasing mitochon-
drial ROS, which initiates a signaling cascade to cause the pathogenic necrosis of myco-
bacterium-infected macrophages. In the context of M.tb infection, TNF-α is also involved
in granuloma formation [142], and with the rise in the use of anti-inflammatory biologics
like TNF-α inhibitors or antagonists, more recent studies have begun to characterize their
roles in the reactivation of latent TB infection (LTBI) [143]. It was recently observed in
human monocytes that TNF-α antagonists differentially induced the TGF-β1-dependent
resuscitation of dormant M.tb [44]. A recent study suggests that CD153, a TNF super fam-
ily member, plays an important role in M.tb control. M.tb-specific CD4+ T cells expressing
CD153 were significantly reduced in patients with active TB when compared to those with
LTBI [45].
IL-6: Interleukin-6 (IL-6) is a cytokine produced by several cell types, including mac-
rophages, and is characterized to have both pro-inflammatory and anti-inflammatory
functions [144,145]. Additionally, IL-6 is involved in processes such as acute phase re-
sponse, cell growth and differentiation, and metabolic functions [146,147]. Given the ple-
otropic nature of IL-6, its role in TB infection remains less clear. For example, IL-6-deficient
mice were highly susceptible to M.tb infection [46]. On the other hand, there is also evi-
dence in the mouse model which suggests that IL-6 secreted by M.tb-infected macro-
phages inhibits the response of uninfected macrophages to IFN-γ [47]. A recent mouse
study reported a novel IL-6 signaling mechanism where myeloid cell-like transcript 2
(TLT2) promotes IL-6 expression through the activation of STAT3 and the blocking of
TLT2 results in a decreased bacterial load [148]. Further mechanistic studies also show the
M.tb virulence factor, Rv3246c, enhances bacterial survival in macrophages by inhibiting
TNF-α and IL-6 production in an NF-κB pathway-dependent manner [48]. To date, there
are a limited number of reports and explanations on the role IL-6 plays directly in the
immune response to TB. More experimentation is needed to fully understand its role, par-
ticularly in the context of human macrophages.
GM-CSF: Granulocyte-macrophage colony-stimulating factor (GM-CSF) has a well-
characterized role in myelopoiesis. More recently, it has generated interest for its role in
tissue inflammation and M.tb infection [149]. A recent study reported GM-CSF to have the
ability to skew macrophages to an M1 phenotype and effectively secrete pro-inflamma-
tory cytokines [150]. In vitro studies show that targeting GM-CSF via monoclonal anti-
bodies results in decreased IL-12p40 and TNF-α production upon BCG infection in mouse
BMDMs [151]. Additionally, in both mouse and human macrophages, GM-CSF enhances
M.tb localization in acidic compartments, resulting in phagolysosomal fusion and bacte-
rial clearance [49,50]. Interestingly, following M.tb infection, human alveolar macro-
phages produce more GM-CSF conferring to them a higher capability to control infection
when compared to mouse macrophages [51]. Additionally, blocking GM-CSF in human
MDMs allows for an increase in bacterial growth, which further highlights a role for GM-
CSF in bacterial control [49]. In the mouse model, the neutralization of GM-CSF in TNF-
α-deficient mice with suboptimal isoniazid/rifampin treatment impairs the host inflam-
matory response and consequently leads to a high number of intracellular M.tb bacilli
[151]. Given the recent findings and novel aspects of GM-CSF function, more attention
should be given to its potential host-directed therapeutic applications.
IL-1β: The pro-inflammatory cytokine IL-1β is believed to play an important role in
protecting the host against M.tb infection. Early studies with IL-1β-deficient mice showed
that its absence leads to mycobacterial outgrowth in the lungs and distant organs, im-
paired granuloma formation, and a lack of Th1-mediated immune response [52]. Addi-
tionally, in the mouse model, the absence of the IL-1R signal leads to a dramatic early
Pathogens 2022, 11, 1153 11 of 25
defect in the early control of M.tb infection due to an absence of MyD88-dependent sig-
naling [53]. In a recent study, IL-1β was linked to limiting M.tb growth in mouse alveolar
macrophages since its absence leads to a delay in the activation of the Th1 response [152].
Another recent study characterized a protective mechanism in which mice treated with β-
glucan showed protection against pulmonary M.tb, and the mechanism was thought to be
mediated via IL-1β signaling [153]. The interplay between M.tb-infected macrophages and
macrophage metabolic processes has been tied to IL-1β since the anti-inflammatory mi-
croRNA-21 (miR-21), produced in response to proliferating mycobacteria, dampens gly-
colysis and causes the downregulation of IL-1β via an immunometabolic mechanism in
mouse BMDMs [154]. A clinical study showed that macrophages with specific IL-1β re-
sponses differed between LTBI cases and active TB patients. Both IL-1β gene and protein
expression were decreased in active TB patients when compared to LTBI subjects suggest-
ing a potential role for IL-1β in preventing TB reactivation [54]. M.tb has evolved with
adaptive capabilities to promote survival. A recent study characterizes a mechanism in
which modern lineages of M.tb produce more IL-1β when compared to isolates of ancient
lineages, thereby promoting IL-1β-induced autophagy, which is paradoxically associated
with a high rate of intracellular bacilli replication [155].
Type I Interferons: The type I interferon family is composed of IFN-α (13 subtypes)
and IFN-β, and these Interferons are classically associated with host defense in viral in-
fections [156]. A role for type I IFNs in TB infection was established in a transcriptomic
study of active TB patients, where the TB signature was dominated by a neutrophil-driven
IFN-inducible gene profile, consisting of both IFN-γ and type I IFN-αβ signaling [157].
Since then, studies in the mouse model predominantly propose that type I IFNs play a
detrimental role during TB infection. A recent study showed that the congenic mouse
strain, B6.Sst1, which carries the “super susceptibility to tuberculosis 1” region of mouse
chromosome 1 from C3HeB/FeJ mice on an otherwise B6 genetic background [158], was
more susceptible to M.tb due to the uncontrolled production of type I IFN [55]. Interest-
ingly, lung lesions in congenic sst1-susceptible mice show extensive necrosis and the un-
restricted extracellular multiplication of M.tb [159]. In murine BMDMs, IFN-β signaling
promotes host protection against M.tb infection by increasing the production of NO [58].
A recent study in murine BMDMs reports that type I IFN signaling correlates with de-
creased glycolysis and mitochondrial damage induced by M.tb, and the absence of type I
IFN signaling allows for glycolytic flux and mitochondrial dysfunction both in in vivo and
in vitro M.tb infections in macrophages [160]. Additionally, in the mouse model, the ab-
sence of type I IFN signaling in combination with Rifampin treatment leads to a significant
reduction in CFUs in lungs and liver when compared to Rifampin alone [56]. In humans,
several studies suggest that patients with active TB have increased levels of type I IFN
and that this correlates with disease severity and poor clinical outcomes [57]. However,
there are also clinical reports indicating a protective role of type I IFN. For example, type
I IFN co-administration with antimycobacterial chemotherapy has been utilized clinically
to treat MDR-TB, resulting in the improvement of clinical symptoms with a reduced bac-
terial burden [161]. Given the evolving mechanistic and clinical contradictory data, more
research is needed to further characterize type I IFN-mediated signaling cascades that ap-
pear to be context-and species-dependent.
IFN-γ: Interferon-γ (IFN-γ) is a type II Interferon and is primarily produced by CD4+
and CD8+ T cells [162]. It has long been thought that IFN-γ plays an important role in host
defense against M.tb and nontuberculous mycobacterial pathogens by activating macro-
phages [162]. IFN-γ is an integral part of antibacterial signaling activities such as granu-
loma formation and phagosome-lysosome fusion, both of which lead to the control of in-
tracellular mycobacteria. In human cells, reduced IFN-γ production is a marker of severe
TB disease and is also utilized for the detection of M.tb infection [163]. Furthermore, IFN-
γ has been linked with limiting intracellular bacterial replication by reducing hepcidin
secretion in THP1 cells [59]. There is also recent evidence to suggest that IFN-γ regulates
metabolic function by promoting glycolysis through inhibiting microRNA 21 (miR-21) in
Pathogens 2022, 11, 1153 12 of 25
mouse BMDMs during M.tb infection [154]. Additionally, mouse models show that IFN-
γ depletes intracellular histidine, which is essential for M.tb survival [60]. Research con-
tinues on the important roles that IFN-γ plays in limiting M.tb growth in macrophages.
IL-10: Interleukin 10 (IL-10) was originally characterized as a chemokine with pre-
dominantly anti-inflammatory properties that impede pathogen clearance by inhibiting
Th1 cells, NK cells, and macrophages [164]. During M.tb infection, IL-10 production in
macrophages is upregulated via the TLR2-ERK pathway [61]. The binding of IL-10 to its
receptor activates a major JAK1-TYK2-STAT3 signaling cascade, which promotes the in-
duction of the STAT3-mediated anti-inflammatory response, diminishing antibacterial ac-
tivity [62]. Additionally, several mouse studies have characterized IL-10 activity, which
allows M.tb to evade the host immune response and suppress macrophage function [165].
IL-10 has been previously targeted as a host-directed therapy via the IL-10-STAT3 path-
way [166]. Furthermore, in M.tb-infected human macrophages, IL-10 has been shown to
block phagosome maturation [63], resulting in increased bacterial survival. In contrast,
evidence from an in vitro study shows that alveolar lining fluid (ALF) in culture promotes
the release of M.tb cell wall fragments, resulting in the production of IL-10, which, coupled
with STAT3 signaling, leads to the macrophage-mediated control of M.tb growth [64].
These contradictory results provide clues for how variables such as environment, location,
and timing influence IL-10 signaling and its downstream consequences on infection biol-
ogy.
TGF-β: TGF-β, produced by monocytes, has been well characterized as a driver of
tissue repair. TGF-β also induces oxidative stress and promotes cell death [167]. A model
has been recently reported that the presence of TGF-β in TB granulomas inhibits the kill-
ing of infected macrophages by cytotoxic T cells [65]. Additionally, in vitro granuloma
studies have established that Adalimumab (ADA), an anti–TNF-α–targeting molecule,
specifically mediates the TGF-β1-dependent resuscitation of dormant-like M.tb [44]. How-
ever, further delineation of the underlying mechanisms for TGF-β’s activities is needed.
IL-12: IL-12 is produced by dendritic cells and macrophages in response to M.tb [168].
Several studies propose a central role of IL-12 in mounting an immune response and the
intracellular killing of pathogens. It has been reported that IL-12p70 promotes macro-
phage bactericidal activity, proliferation, and cytosolic activity [66]. Several studies have
reported that mutations in IL-12 confer increased susceptibility to M.tb infection [67]. An-
other study characterized mycobacterial genetic mutations leading to the modification of
cell wall mycolic acids that results in the enhancement of IL-12 release by macrophages
[169]. Given its central role in host defense, it makes sense that M.tb has developed im-
mune evasion strategies that target IL-12 function.
10. Immune Factors: Chemokines
Chemokines play an important role in orchestrating the recruitment of cells includ-
ing macrophages into the M.tb-infected lung, which contributes to M.tb containment but
also can harm the host by contributing to inflammation and cavitation in the lungs during
disease progression [68]. Plasma chemokines can be used as biomarkers of disease sever-
ity, higher bacterial burden, and delayed sputum culture conversion in pulmonary TB
[170]. A plasma chemokine signature can also be used as a novel biomarker for predicting
adverse treatment outcomes in pulmonary TB [171]. A recent study [69] identified that the
baseline levels of plasma chemokines CCL1, CCL3, CXCL1, CXCL2, and CXCL10 were
significantly higher in active TB (both microbiologically confirmed and clinically diag-
nosed TB) in comparison to TB controls in children. Consequently, these findings suggest
that these chemokine signatures could also serve as biomarkers for the diagnosis of pedi-
atric TB [69].
11. Host Genetic Factors
Previously, we and others have reviewed polymorphisms in genes of a wide variety
of host innate immune factors associated with TB risk or resistance [172,173]. Here, we
Pathogens 2022, 11, 1153 13 of 25
focus only on recent reports of selected classes in which host innate immune factors have
been linked to susceptibility to or protection from TB (Table 2).
Table 2. Innate Immune Gene Polymorphisms that Affect Macrophage Response and TB Disease in
Populations.
Gene Polymorphism Population
Association
with TB Effect Reference
IFN-γ +874 T/A (rs2430561)
American, European, Af-
rican, Asian
Yes Susceptible [174]
TNF
rs1799964,
rs1800630 Chinese Tibetan Yes Susceptible [175]
rs1799724,
rs1800629 Tibetan Yes Susceptible [175]
IL-1β
rs16944
Chinese Han, Tibetan
Yes
Protective
[175]
IL-6
rs2069837
Chinese Han
Yes
Protective
[175]
IL-17A
rs8193036
Chinese Han
Yes
Susceptible
[176]
REL/IL-12
rs842618
Vietnamese
Yes
Susceptible
[177]
BHLHE40/
IL-10
rs11130215 South Africa Yes Protective [177]
TLR8
rs3764880
Chinese Han
Yes
Protective
[178]
TLR9
rs187084
Chinese Han
Yes
Susceptible
[178]
TLR2
rs3804099,
rs3804100
Han Taiwanese
Yes Susceptible [179]
NOD2
rs1861759,
rs7194886
Chinese Han Yes Susceptible [180]
rs2066842,
rs2066844
African Americans Yes Protective [180]
CD14
rs2569190,
rs2569191
Chinese Han Yes Susceptible [180]
Mincle
(CLEC4E)
rs10841847 West African Yes Susceptible [181]
MARCO
rs12998782
Chinese Han
Yes
Susceptible
[182]
CD36
rs1194182,
rs10499859
Chinese Han Yes Protective [182]
VDR
Fok1(T/C) genotype
North Indian
Yes
Susceptible
[183]
Folk1(ff) genotype
Chinese
Yes
Susceptible
[184]
BsmI (rs1544410)
TaqI (rs731236),
Iranian Yes Susceptible [185]
CARD8
rs2043211
Ethiopian
Yes
Susceptible
[186]
NLRP3
rs35829419
Ethiopian
Yes
Susceptible
[186]
AIM2
rs1103577
Brazilian
Yes
Protective
[187]
MASP1
rs3774275
Indian
Yes
Protective
[188]
MBL2
A/O, O/O genotype
Polish
Yes
Susceptible
[189]
SP-D
rs721917
Taiwanese
Yes
Susceptible
[190]
SP-A
rs17886395,
rs1965707
Chinese Han Yes Susceptible [191]
NRAMP
5'(CA)
n
, INT4, D543N,
and 3'UTR
African, American Yes Susceptible [192,193]
3'UTR
Indian
Yes
Susceptible
[194]
Pathogens 2022, 11, 1153 14 of 25
11.1. Cytokines
Changes in the production and release of cytokines affecting macrophage function
are often linked to TB susceptibility or protection. For example, a systematic meta-analysis
exploring the association between IFN-γ polymorphisms and the risk of developing TB
found that there is an association between IFNG-γ +874 T/A (rs2430561) and the develop-
ment of disease [174]. Another study found that single nucleotide polymorphisms (SNPs)
in TNF were associated with protection against TB due to increased TNF expression and
secretion [175]. A cohort study reported SNPs in TNF, IL-6, and IL-1β that possibly af-
fected the levels of these cytokines and led to susceptibility or protection against TB infec-
tion [175]. An SNP in IL-17 that resulted in decreased IL-17A production upon stimulation
was associated with TB susceptibility in a Chinese Han population [176]. Interestingly, a
study that examined the master regulators of IL-12 and IL-10 signaling found that variants
resulting in the increased production of IL-12 were associated with susceptibility to TB
but an SNP that resulted in increased IL-10 production was associated with decreased
pediatric TB [177]. In conclusion, variations in cytokine responses resulting from their ge-
netic polymorphisms can lead to the enhanced or decreased control of TB infection, alt-
hough it is important to note that too much of a cytokine can also be as detrimental as too
little. Linking these polymorphisms specifically to defects in macrophage immune re-
sponse awaits further studies.
11.2. Receptors
Differences in the activities of the cellular receptors, especially of macrophages, that
recognize M.tb for uptake and that are associated with TB pathogenesis have also been
identified. A case-control study of a Chinese Han cohort identified SNPs in PRRs, TLR8,
and TLR9, which were found to be associated with the development of TB [178]. In an-
other study with a Han Taiwanese population [179], the C-T haplotype in the TLR2 gene,
in comparison with the most common T-T haplotype, was associated with an increased
risk for TB. There is evidence to justify further evaluation of TLR2 polymorphisms and
their effect on TLR2-dependent signaling as these findings can provide insight into the
development of TB therapeutics [195]. Mutations in NOD2, an intracellular PRR that rec-
ognizes TB, were also identified and associated with increased susceptibility [180]. Studies
on another PRR, Mincle or CLEC4E, have also been conducted and the results suggest the
influence of ethnicity on the presence of significant polymorphisms in this receptor
[181,196]. SNPs in MARCO and CD36, two scavenger receptors, have been found related
to pulmonary TB risk [182]. Lastly, although not a receptor involved in the phagocytosis
or uptake of M.tb, multiple recent studies have examined polymorphisms in the vitamin
D receptor (VDR) in different populations for their association with increased susceptibil-
ity to TB infection [183–185,197]. Other important immune factors in which SNPs have
been recently studied include NLRP3 [186], AIM2 [179,187], and C-type lectins [188,189].
11.3. Collectins (SP-A and SP-D)
Collectins are collagen-containing calcium-dependent (C-type) lectins that function
to assist in the clearance of pathogens and particles in the lungs. Surfactant proteins A
(SP-A) and D (SP-D) are collectins that are expressed by alveolar type II epithelial cells.
Both SP-A and SP-D have been shown to be involved in regulating the phagocytosis of
M.tb by macrophages [198,199]. Additionally, SP-D has been shown to reduce the intra-
cellular growth of M.tb in macrophages [200]. A case-control study employing an in vitro
assay illustrated that an SP-D polymorphism had the lower binding ability and less inhi-
bition of the intracellular growth of M. bovis BCG in a murine alveolar macrophage cell
line (MH-S cells) [190]. A measurement of allelic mRNA expression imbalance in collectins
and several C-type lectin genes from human lung tissues revealed a frequent regulatory
SNP in the SP-A gene in our own study [201]. In the Chinese Han population, both disease
risk and protective correlations were reported between the presence of SNPs in the SP-A
Pathogens 2022, 11, 1153 15 of 25
gene and pulmonary TB [191]. Apart from genetic polymorphisms, there is evidence to
support that aging plays a role as macrophages infected with M.tb that had been exposed
to alveolar lung fluid from elderly individuals (E-ALF) are less capable of controlling M.tb
due to dysfunctional SP-A and SP-D in the E-ALF[202]. Similarly, mice infected with M.tb
exposed to E-ALF displayed a significantly higher bacterial burden in the lung [202].
11.4. NRAMP1
The Natural Resistance-Associated Macrophage Protein 1 (NRAMP1) gene produces
an integral membrane protein that functions as a divalent ion channel for transporting
metals [203]. This protein is expressed exclusively in the lysosomal compartment of mon-
ocytes and macrophages and, after phagocytosis, NRAMP1 is targeted to the microbe-
containing phagosomal membrane where it controls intracellular microbial replication by
actively removing iron or other divalent cations from the phagosomal site [204]. Several
studies have characterized the association of NRAMP1 with TB susceptibility in different
parts of the world [192,193]. Recently, a case-control study in India analyzing the effects
of a polymorphism in the NRAMP1 gene (3’UTR) showed an increase in host susceptibil-
ity to TB [194].
Overall, more follow-up work remains to be performed on elucidating the mecha-
nisms by which genetic variants in innate immune factors, especially with regard to mac-
rophages, result in protection or susceptibility to TB and how this can broaden our under-
standing of the interplay between host and pathogen.
Conclusion
TB remains one of the most lethal infectious diseases in the world. There has been a
surge of research on cellular and biochemical pathways that are important in advancing
our understanding of how M.tb has evolved to thrive in its intracellular niche, macro-
phages. The previously unknown roles of various novel proteins and small molecules
from both host and pathogen in TB infection have also recently been described. In this
review, we discuss several recent host innate immune macrophage factors as well as mi-
crobiological factors that play crucial roles during in vitro and in vivo infection by M.tb in
either controlling or promoting bacterial survival in macrophages. Given the importance
of innate immune factors like cytokines and bioeffector molecules in the host response to
TB, work continues on characterizing the effects of their signaling cascades on the inflam-
matory response and its resolution. Mutations or SNPs in the genes for cytokines and
other important molecules continue to be described, although much work remains to un-
cover the functional mechanisms by which these SNPs exert their effects. Besides varia-
tions in host genetics, differences in infecting M.tb strains and other microbiological fac-
tors that influence M.tb fitness offer additional insight into the pathogenesis and response
of TB. Since TB infection remains a global public health problem in an era of increasing
antibiotic resistance, we contend that a more comprehensive understanding of different
immune factors that promote bacterial growth or protect against M.tb growth in macro-
phages will allow for the development of novel approaches for host-directed therapies
that augment the activity of antibiotics against this deadly disease.
Author Contributions: Conceptualization, L.S.S. and A.K.A.; software, J.D.S.; investigation, L.S.S.,
A.K.A., J.D.S. and E.P.; writing-original draft preparation, J.D.S., E.P. and A.K.A.; writing-review
and editing, A.K.A. and L.S.S.; visualization, E.P. and J.D.S.; supervision, L.S.S. and A.K.A.; funding
acquisition, L.S.S. and J.D.S.
All authors have read and agreed to the published version of the manuscript.
Funding: The authors’ work in the Schlesinger laboratory was supported by the National Institutes
of Health (NIH) grant numbers R01 AI-136831, R21 AI-145539, and P01 AG-051428. J.D.S was sup-
ported by the NIH pre-doctoral training grant number T32 GM-11383896.
Institutional Review Board Statement: Not applicable.
Pathogens 2022, 11, 1153 16 of 25
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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