Figure - available from: Journal of Immunology Research
This content is subject to copyright. Terms and conditions apply.
Schematic representation of the mechanisms of persistence of selected intracellular pathogens. Left: an overview of the various mechanisms used by pathogens to overcome innate and adaptive immune responses. The major strategies are discussed in more detail in the text. Right: evasion strategies of various phagocytic mechanisms by selected intracellular pathogens. Viruses such as influenza virus are able to inhibit the activation of antiviral mechanisms, such as the production of interferon upon viral infection, and enter the nucleus. Mycobacterium tuberculosis after phagocytosis acquires the early endosome marker Rab5, which blocks fusion with the lysosome, and the mycobacteria replicate in this early endosome. Legionella pneumophila resides and multiplies in vacuoles that acquire Rab1 and secretes effector molecules via its type IV secretion system, which inhibits phagolysosome formation. Listeria monocytogenes-engulfed phagosome undergoes acidification, which perforates the phagosomal membrane and the bacteria escape into the cytosol, where they move within and then among cells with actin polymerization. Chlamydia spp. are present as nonreplicating infectious “elementary body” and intracytoplasmic replicating noninfectious “reticulate body.” The elementary body induces its own endocytosis upon exposure to host cells and survives and multiplies inside phagolysosome before infecting the new host. Coxiella burnetii and Brucella abortus are present inside a vacuole, which becomes acidic and acquires Rab5 followed by Rab7 that prevents phagolysosome formation. The Francisella tularensis phagosome acquires Rab5 (early endosome) and then Rab7 (late endosome). Late endosome is not acidified, which disrupts the phagosomal membrane discharging the bacteria into the cytosol. These vacuoles fuse with the endoplasmic reticulum, which allow bacterial replication. Leishmania spp. phagosome becomes acidic phagolysosome, which bears Rab7, and the parasite survives and multiplies inside the phagolysosome.
Source publication
Infectious diseases caused by pathogens including viruses, bacteria, fungi, and parasites are ranked as the second leading cause of death worldwide by the World Health Organization. Despite tremendous improvements in global public health since 1950, a number of challenges remain to either prevent or eradicate infectious diseases. Many pathogens can...
Citations
... Although R. hoagii is considered an uncommon pathogen for humans, currently, the number of cases reported in the literature has significantly increased due to the increasing presence of immunocompromised individuals, even though infection has also been described less commonly in immunocompetent hosts (15)(16)(17)(18). Deficiencies in cell-mediated immunity constitute the main predisposing factor for infection by this intracellular germ (19). ...
The present study describes the case of a 33-year-old male patient, who was diagnosed with concurrent infections of Rhodococcus hoagii (R. hoagii), Mycobacterium intracel-lulare (M. intracellulare), human immunodeficiency virus (HIV) and syphilis. This patient, a homeless farm laborer with no prior medical treatments, exhibited symptoms including persistent fever and cough, and was admitted to hospital. Treatment was initiated with a combination of anti-retroviral therapy with emtricitabine/tenofovir alafenamide/dolutegravir, and antibiotics (azithromycin, rifampicin, amikacin and ethambutol) targeted at both R. hoagii and M. intracellulare, alongside adjustments for drug-drug interactions due to rifampicin administration. Despite initial improvements and discharge after 21 days with scheduled outpatient follow-ups, the patient did not return for further treatment monitoring. The case presented herein underscores the challenges in managing complex infections in severely immunocompromised patients and highlights the need for integrated treatment approaches, careful drug management, and robust follow-up systems to ensure adherence and prevent relapse. In addition, the present case report contributes to the limited literature available on R. hoagii infections in HIV-infected individuals and highlights the need for early intervention and comprehensive management in similar clinical scenarios.
... The immune response against intracellular pathogens entails a series of intricate steps aimed at detecting and eliminating the invading pathogens [1]. It begins with the recognition of specific pathogen-associated molecular patterns by immune cells, triggering their activation and migration to the site of infection. ...
Identifying antigens within a pathogen is a critical task to develop effective vaccines and diagnostic methods, as well as understanding the evolution and adaptation to host immune responses. Historically, antigenicity was studied with experiments that evaluate the immune response against selected fragments of pathogens. Using this approach, the scientific community has gathered abundant information regarding which pathogenic fragments are immunogenic. The systematic collection of this data has enabled unraveling many of the fundamental rules underlying the properties defining epitopes and immunogenicity, and has resulted in the creation of a large panel of immunologically relevant predictive (in silico) tools. The development and application of such tools have proven to accelerate the identification of novel epitopes within biomedical applications reducing experimental costs. This chapter introduces some basic concepts about MHC presentation, T cell and B cell epitopes, the experimental efforts to determine those, and focuses on state-of-the-art methods for epitope prediction, highlighting their strengths and limitations, and catering instructions for their rational use.
... It is well established that antibodies play a central role in the humeral immunity induced by vaccination, supported by T H cells [95,96]. Antibody responses are generally essential in preventing the establishment of disease [97,98], whereas, in recent years, it has become evident that cytotoxic T cells also play a major role in fighting an infection, by controlling and clearing an already established disease [99,100]. For example, there is ample evidence showing that individuals with inherited or acquired antibody deficiencies have an increased susceptibility to the acquisition of infection, whereas T-cell deficiency results in the failure to control a pathogen after an infection [101][102][103]. ...
Extensively drug-resistant Pseudomonas aeruginosa infections are emerging as a significant threat associated with adverse patient outcomes. Due to this organism’s inherent properties of developing antibiotic resistance, we sought to investigate alternative strategies such as identifying “high value” antigens for immunotherapy-based purposes. Through extensive database mining, we discovered that numerous Gram-negative bacterial (GNB) genomes, many of which are known multidrug-resistant (MDR) pathogens, including P. aeruginosa, horizontally acquired the evolutionarily conserved gene encoding Zonula occludens toxin (Zot) with a substantial degree of homology. The toxin’s genomic footprint among so many different GNB stresses its evolutionary importance. By employing in silico techniques such as proteomic-based phylogenetic tracing, in conjunction with comparative structural modeling, we discovered a highly conserved intermembrane associated stretch of 70 amino acids shared among all the GNB strains analyzed. The characterization of our newly identified antigen reveals it to be a “high value” vaccine candidate specific for P. aeruginosa. This newly identified antigen harbors multiple non-overlapping B- and T-cell epitopes exhibiting very high binding affinities and can adopt identical tertiary structures among the least genetically homologous P. aeruginosa strains. Taken together, using proteomic-driven reverse vaccinology techniques, we identified multiple “high value” vaccine candidates capable of eliciting a polarized immune response against all the P. aeruginosa genetic variants tested.
... Infections of mammalian cells by biological pathogens such as viruses often lead to significant alterations in the subcellular structures of the host cells(Robinson et al., 2018;Thakur et al., 2019). The Japanese encephalitis virus (JEV), a single-stranded positivesense RNA virus belonging to the Flavivirus genus of the Flaviviridae family, is a mosquito-borne zoonotic virus. ...
Cell biologists have long sought the ability to observe intracellular structures in living cells without labels. This study presents procedures to adjust a commercially available apodized phase-contrast (APC) microscopy system for better visualizing the dynamic behaviors of various subcellular organelles in living cells. By harnessing the versatility of this technique to capture sequential images, we could observe morphological changes in cellular geometry after virus infection in real time without probes or invasive staining. The tune-up APC microscopy system is a highly efficient platform for simultaneously observing the dynamic behaviors of diverse subcellular structures with exceptional resolution.
Key words: Label-free imaging, Organelle dynamics, Virus infections, Apodized phase contrast
... Although extracellular bacterial infections are generally easier to treat, intracellular bacteria pose significant threats to human health. Certain microbes can infiltrate host cells to harness cellular resources and conceal themselves from host defenses (11). Other microorganisms, such as Salmonella enterica and Listeria monocytogenes, can adapt their lifestyle to become intracellular for a limited period. ...
... The products released by intracellular bacteria are recognized by Toll-like receptors (TLRs) and Nod-like receptors (NLRs), and activates the effector phagocytic cells (46). Phagocytic cells generally recognize microbes based on unique molecular patterns (PAMPs) in the microorganisms, irrespective of their pathogenicity (11). TLRs are responsible for initiating a response that prompts macrophages to produce proteins and peptides with antimicrobial properties. ...
... Although, simultaneous study of host and microbe genomes increases the complexity, scRNA-seq can elucidate the influence of diverse intracellular microbial species on the composition and host transcriptional profiles of diverse cells. The "dual RNA-seq" studies allow us to investigate both host and pathogen genomes in parallel (11) (102). New state-of-the-art tools have been developed to analyze the single cell transcriptomic datasets to identify intracellular pathogens at the single-cell level (50,51). ...
Host-microbe interactions are complex and ever-changing, especially during infections, which can significantly impact human physiology in both health and disease by influencing metabolic and immune functions. Infections caused by pathogens such as bacteria, viruses, fungi, and parasites are the leading cause of global mortality. Microbes have evolved various immune evasion strategies to survive within their hosts, which presents a multifaceted challenge for detection. Intracellular microbes, in particular, target specific cell types for survival and replication and are influenced by factors such as functional roles, nutrient availability, immune evasion, and replication opportunities. Identifying intracellular microbes can be difficult because of the limitations of traditional culture-based methods. However, advancements in integrated host microbiome single-cell genomics and transcriptomics provide a promising basis for personalized treatment strategies. Understanding host-microbiota interactions at the cellular level may elucidate disease mechanisms and microbial pathogenesis, leading to targeted therapies. This article focuses on how intracellular microbes reside in specific cell types, modulating functions through persistence strategies to evade host immunity and prolong colonization. An improved understanding of the persistent intracellular microbe-induced differential disease outcomes can enhance diagnostics, therapeutics, and preventive measures.
... Pathogens can modulate the immune system to survive and multiply in their hosts. The release of antigens as secreted immunomodulators is one of the strategies used by microbes, such as intracellular ones [24], to change the immune equilibrium in their favor, which includes Paracoccidioides fungi [25]. Our group has shown that rHSP60 can cause deleterious effects in mice treated with one application of rHSP60 without showing the precise mechanism [15], in contrast to protection developed when used in 3-dose schedules of vaccination [17] or therapy [15]. ...
Paracoccidioides fungi are thermodimorphic microorganisms that cause paracoccidioidomycosis (PCM), an autochthonous disease from Latin America, with most cases in Brazil. Humans become infected by inhaling conidia or mycelial fragments that transform into yeast at body temperature. These fungi cause chronic-granulomatous inflammation, which may promote fibrosis and parenchyma destruction in the lungs. In response to stress imposed by the host, fungi Paracoccidioides spp. increase the expression of heat shock proteins (HSP), which protect them by sustaining cellular proteostasis. Our group has studied the role of HSP60 in PCM, and previous data show that the recombinant HSP60 (rHSP60) has a deleterious effect when used in a single dose as therapy for experimental PCM. Here, we investigated the mechanism by which rHSP60 could worsen the disease. We found that rHSP60 caused the viability loss of splenic or lymph node cells from both immunized and non-immunized mice, including in splenic T lymphocytes under polyclonal stimulation with concanavalin A, probably by undergoing apoptosis. Among analyzed splenic cells, lymphocytes were indeed the main cells to die. When we investigated the death mechanisms, remarkably, we found that there was no viability loss in rHSP60-stimulated splenic cells from mice deficient in Toll-like receptor 4, TRIF adapter protein, and TNF receptor 1(TNFR1), as well as rHSP60-stimulated WT cells incubated with anti-TNF antibody. Besides, caspase-8 inhibitor IETD-CHO blocked the rHSP60 effect on splenic cells, suggesting that rHSP60 induces the extrinsic apoptosis pathway dependent on signaling via TLR4/TRIF and TNFR1.
... Intracellular pathogens deploy various strategies to enhance their survival and avoid clearance from the host [73,74]. Several studies show that C. burnetii infection arrests the apoptotic pathway in HeLa, CHO, and THP-1 cells during early-stage infection (1-2 dpi) [32,37,38]. ...
STING (STimulator of Interferon Genes) is a cytosolic sensor for cyclic dinucleotides (CDNs) and initiates an innate immune response upon binding to CDNs. Coxiella burnetii is a Gram-negative obligate intracellular bacterium and the causative agent of the zoonotic disease Q fever. The ability of C. burnetii to inhibit host cell death is a critical factor in disease development. Previous studies have shown that C. burnetii inhibits host cell apoptosis at early stages of infection. However, during the late-stages of infection, there is host cell lysis resulting in the release of bacteria to infect bystander cells. Thus, we investigated the role of STING during late-stages of C. burnetii infection and examined STING’s impact on host cell death. We show that the loss of STING results in higher bacterial loads and abrogates IFNβ and IL6 induction at 12 days post-infection. The absence of STING during C. burnetii infection significantly reduces apoptosis through decreased caspase-8 and -3 activation. During infection, STING activates IRF3 which interacts with BAX. BAX then translocates to the mitochondria, which is followed by mitochondrial membrane depolarization. This results in increased cytosolic mtDNA in a STING-dependent manner. The presence of increased cytosolic mtDNA results in greater cytosolic 2′-3′ cGAMP, creating a positive feedback loop and leading to further increases in STING activation and its downstream signaling. Taken together, we show that STING signaling is critical for BAX-IRF3-mediated mitochondria-induced apoptosis during late-stage C. burnetii infection.
... Macrophages play a crucial role in phagocytosing foreign particles and microbes, which then merge with lysosomes to form phagolysosomes (Ahsan et al., 2002;Patel et al., 2015). However, certain intracellular pathogens have developed strategies to evade phagolysosome fusion, making it challenging to deliver drugs effectively at therapeutic concentrations (Stanley and Cox, 2013;Thakur et al., 2019;Verma et al., 2022). The subcellular localization of PPEF.3HCl formulations was tracked by confocal microscopy. ...
... Our investigation revealed that the frequency of CD4+GATA3+ cells was significantly decreased in both hospitalized patient groups compared to the HC. (16). ...
... Th1 cells play a crucial role in combating intracellular pathogens, primarily secreting IFNγ and IL2. IFNγ is essential for activating macrophages to enhance their phagocytic activity, while Th17 cells are necessary to stimulate an immune response against extracellular bacteria and fungi (16). Moreover, the frequencies of blood CD4+ and CD8+ T cells were significantly reduced in ICU severe COVID-19 patients (23). ...
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes immune system dysregulation and a systemic cytokine storm. Under healthy conditions, T helper cells protect against intracellular pathogens, extracellular parasites, and extracellular bacteria. Objectives: For the novelty of our study, little is known regarding the balance of T cell subtypes and responses in two forms of COVID-19 in our country. We investigated whether there was a relationship between T cell subtype frequency and cytokines by COVID-19 severity. Methods: Forty-six PCR-confirmed severe (n = 30) and moderate (n = 16) COVID-19 patients and 13 sex- and age-matched healthy control (HC) subjects were enrolled. Immunophenotyping of T cell subsets and related serum cytokines was performed using flow cytometry and ELISA, respectively. Results: There was a significantly lower frequency of CD8+Tbet+ (P < 0.01) T cells in the severe group compared to HC. Also, there was a significantly lower frequency of CD4+GATA3+ (P < 0.001) and CD8+Tbet+ (P < 0.001) T cells in the severe group compared to the moderate group. Moreover, receiver-operating characteristic (ROC) curve analysis revealed a considerable correlation between CTL (CD8+T-bet+) subtypes and the severity of the disease. Severe COVID-19 disease was associated with reduced interferon-gamma (IFN-γ) and interleukin (IL)-2 concentration and increased IL-5 and IL-6 concentration. Conclusions: Reduced systemic levels of IL-2 can trigger decreased numbers of Th1 and Th2 cells, and in contrast to elevated IL-5 and IL-6, the numbers of Th2 cells did not increase in these cases.
... These bacteria have proven good and bad impacts on human health. While the majority of these are quite helpful a few of these causes' death alarming diseases (Thakur et al., 2019). A fine example of bacterial pathogenesis is Mycobacterium tuberculosis infection (Schmidt and Hensel, 2004). ...
... Infections caused by intracellular bacteria include brucellosis, listeriosis, tuberculosis, and salmonellosis (Silva, 2012;Jiao et al., 2021). These pathogens use various pathways to enter host cells, such as macrophages, phagocytes, epithelial and endothelial cells, and hepatocyte (Kaufmann, 1993;Thakur et al., 2019). Some may also transmit intercellularly without an . ...
Bacteria are the most prevalent form of microorganisms and are classified into two categories based on their mode of existence: intracellular and extracellular. While most bacteria are beneficial to human health, others are pathogenic and can cause mild to severe infections. These bacteria use various mechanisms to evade host immunity and cause diseases in humans. The susceptibility of a host to bacterial infection depends on the effectiveness of the immune system, overall health, and genetic factors. Malnutrition, chronic illnesses, and age-related vulnerabilities are the additional confounders to disease severity phenotypes. The impact of bacterial pathogens on public health includes the transmission of these pathogens from healthcare facilities, which contributes to increased morbidity and mortality. To identify the most significant threats to public health, it is crucial to understand the global burden of common bacterial pathogens and their pathogenicity. This knowledge is required to improve immunization rates, improve the effectiveness of vaccines, and consider the impact of antimicrobial resistance when assessing the situation. Many bacteria have developed antimicrobial resistance, which has significant implications for infectious diseases and favors the survival of resilient microorganisms. This review emphasizes the significance of understanding the bacterial pathogens that cause this health threat on a global scale.
