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Clinical Research and Studies Page 8 of 8
The Role of Host Genetics in the Immune Response to Sars Cov-2 and
covid-19 Susceptibility and Severity
Bantayehu Bekele Made 1*, Dereje Beyene 2
1 PhD student (Applied Genetics) at Addis ababa university.
2 Associate professor at Addis ababa university.
*Corresponding Author: Bantayehu Bekele Made, Clinical Psychologist, Shahid Beheshti University of medical sciences, Loghman Hakim
hospital, Tehran, Iran.
Received date: October 07, 2022; Accepted date: October 18, 2022; Published date: October 27, 2022
Citation: Bantayehu Bekele Made, Dereje Beyene (2022). The Role of Host Genetics in the Immune Response to Sars Cov-2 and covid-19
Susceptibility and Severity. Clinical Research and Studies, 1(2) DOI:10.31579/2835-2882/006
Copyright: © 2022 Bantayehu Bekele Made, This is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Several seasonal coronaviruses are known to circulate in the human population including alpha coronaviruses HCoV-
NL63 and HCoV-229E, and the beta corona viruses HCoV-OC43 and HCoV-HKU1. Moreover, since 2003 three other
corona viruses such as SARS-CoV-1: the severe acute respiratory syndrome coronavirus; MERS-CoV: the Middle East
respiratory syndrome [MERS] coronavirus; and SARS-CoV-2: the causative agent of COVID-19) have emerged as
human pathogens. It become one of the leading pathogens of the latest emerging outbreaks of respiratory disease,
representing a serious public health burden worldwide. Studies show that Sars-Cov-2 is more infectious than SARS-
CoV this is due to higher binding affinity of RBD to ACE2, less exposed RBD (immune escape), and pre-activation by
furin (enhanced viral entry). A wide range of disease severity occurs in the patients’ experiences, from asymptomatic
cases, mild infections to serious life threatening conditions requiring admission into the intensive care unit (ICU).
Although, it is generally reported that age and co-morbidities contribute significantly to the variations in the clinical
outcome of the scourge of COVID-19, a hypothetical question of the possibility of genetic involvement of ACE2, HLA,
and TLR genes such as TLR7 and TLR3 in the susceptibility and severity of the disease arose when some unique severe
outcomes were seen among young patients with no co-morbidity.
Keywords: sars cov-2; covid-19; host genetics; susceptibility; severity
Introduction
Several seasonal coronaviruses are known to circulate in the human
population and generally cause relatively mild respiratory tract infections,
including the alpha coronaviruses HCoV-NL63 and HCoV-229E, and the
beta corona viruses HCoV-OC43 and HCoV-HKU1, phylogenic evidence
show their origin were from bat(NL63 and 229E) or rodent-associated
(OC43 and HKU1) coronaviruses (Inna et al., 2020). Furthermore, since
2003 three additional coronaviruses (i.e., SARS-CoV-1: the severe acute
respiratory syndrome coronavirus; MERS-CoV: the Middle East
respiratory syndrome [MERS] coronavirus; and SARS-CoV-2: the
causative agent of COVID-19) have emerged as human pathogens, and
each is associated with severe infection) (Inna et al., 2020).
Coronaviruses (CoVs) have become one of the leading pathogens of the
latest emerging outbreaks of respiratory disease, representing a serious
public health burden worldwide (Inna et al., 2020). A novel coronavirus
was identified to play a crucial role in the severe acute respiratory
syndrome (SARS) in 2003 (Arnold, 2020). Later, the severe acute
respiratory syndrome coronavirus-2 (SARSCoV-2), which produces the
disease coronavirus-2019 (COVID-19), has emerged in December 2019.
This novel virus appears to be highly contagious and has spread rapidly
throughout the world, reaching a pandemic state, with important social
and health system costs (Adeboboye et al., 2020). Studies show that
SARS-CoV-2 is more infectious than SARS-CoV, which may explain
why SARS-CoV-2 has caused a more severe pandemic than SARSCoV.
Three mechanisms which have been proposed to potentially play a role in
this increased SARS-CoV-2 infectivity are: (1) higher binding affinity of
RBD to ACE2, (2) less exposed RBD (immune escape), and (3) pre-
activation by furin (enhanced viral entry) (Huang and Wang, 2021).
Subsequently, a wide range of clinical outcomes have been observed
among individuals diagnosed with COVID-19, ranging from mild
respiratory infection to acute respiratory disease and death. Disease
severity is disproportionately higher among older adults and individuals
with underlying comorbidities, although severe cases of COVID-19 have
also been reported among young and healthy individuals (Inna et al.,
2020).
Since the start of the current SARS-CoV-2 pandemic, scientists have been
puzzling over the factors underlying the inter individual and inter-
population differences in disease outcomes (Adeboboye et al., 2020). The
Open Access
Review Article
Clinical Research and Studies
Bantayehu Bekele Made *
*
ClinicSearch
Clinical Research and Studies Page 2 of 9
resulting clinical manifestation of COVID-19 varied enormously, ranging
from mild/asymptomatic illness in 80% of patients to a severe respiratory
syndrome in 20%, which further progresses to critical illness requiring
ventilation in 5% (Adeboboye et al., 2020). For instance in-vivo studies
of the angiotensin-converting enzyme 2 (ACE 2) showed higher
expression in the kidneys of male than female patients, which may explain
the differences in susceptibility and progression of COVID-19 between
male and female patients. Ethnic groups often have higher levels of
medical comorbidities and lower socioeconomic status, which may
increase their risk of contracting COVID-19 through weak cell-mediated
immunity (Koppel J. et al., 2020). A recent study noted that ACE2
expression could vary among Asians (significantly higher) compared to
African Americans and Caucasians (Zhao Y. et al., 2020).
Previously, the focuses of most studies were on the clinical
characteristics, epidemiology, and genomic characterization of SARS-
CoV-2 infection. Only few studies were carried out regarding to the role
of host genetics in influencing susceptibility and severity of COVID-19.
Individuals in the population harbor single nucleotide polymorphisms
(SNPs) across a variety of genes (eg, ACE2, TMPRSS2, HLA, CD147,
MIF, IFNG, IL6) that have been implicated in the pathology and
immunology of SARS-CoV-2 and other pathogenic coronaviruses (Inna
et al., 2020). These and other genetic variants may modulate disease
susceptibility, increase or decrease disease severity, alter the variety of
symptoms developed, and affect the magnitude and/or quality of the
immune responses against SARS-CoV-2 (Inna et al., 2020). The current
review aim was to discuss the recent findings regarding the role of host
genetics to susceptibility and development of severity to Sars cov-2
infection.
Origin and Biology of Sars Cov-2
Origin of Sars Cov-2
Before first detected in December 2019, COVID 19 was inferred to be
present in Hubei province, China, for about a month before (Lytras S. et
al., 2021). To understand its origin, it is necessary to go back to 2002.
During that period, a novel respiratory coronavirus (SARS-CoV)
appeared in Foshan, Guangdong province, China, and spread to 29
countries before public health measures controlled its spread in 2003. The
zoonotic origin of SARS-CoV was subsequently linked to live animals
available at markets. Further sporadic spill-over events of SARS-CoV
from animals took place in Guangzhou, Guangdong, and some
researchers working with cultured virus were infected in laboratory
accidents (Song et al., 2005), but ultimately SARS-CoV was removed
from the human population. Trading of susceptible host animals is an
important common theme in the emergence of SARS and COVID-19
(Lytras S. et al., 2021).
After three years of SARS epidemic began, Studies show that horseshoe
bats (Rhinolophus) in China were harboring related coronaviruses (Li et
al., 2005). SARS-related coronavirus (SARSr-CoV) comprises the
Sarbecovirus subgenus of the Betacoronavirus genus. It was inferred that
a sarbecovirus circulating in horseshoe bats seeded the progenitor of
SARS-CoV in an intermediate animal host, most probably civet cats.
Further raccoon dogs and badgers were identified as possible intermediate
i.e. to have acted as the conduits of transmission to humans from the
horseshoe bat reservoir of SARS-CoV, rather than civet cats being a long-
term reservoir host species. On the other way, Wuhan Institute of
Virology (WIV) in Hubei was speculated as the source of the pandemic
because no SARS-CoV-2 intermediate host has been identified to date
and owing to the WIV’s geographic location (Lytras S. et al., 2021).
Figure 1: Horseshoe bats, (Rhinolophus ferrumequinum)
Wuhan city were the origin of SARS-CoV-2 and located at 1500km away
from Yunnan province, from where the closest known naturally occurring
sarbecovirus collected from horseshoe bats. How did SARS-CoV-2 arrive
in Wuhan? Since its emergence, sampling has revealed that coronaviruses
genetically close to SARS-CoV-2 are circulating in horseshoe bats, which
are dispersed widely from East to West China, and in Southeast Asia and
Japan (Lytras S. et al., 2021). The wide geographic ranges of the potential
reservoir hosts—for example, intermediate (R. affinis) or least (R.
pusillus) horseshoe bat species, which are known to be infected with
sarbecoviruses—indicate that the singular focus on Yunnan is misplaced
(Lytras S. et al., 2021). Confirming this assertion, the evolutionarily
closest bat sarbecoviruses are estimated to share a common ancestor with
SARS-CoV-2 at least 40 years ago (Lytras S. et al., 2021), showing that
these Yunnan-collected viruses are highly divergent from the SARS-
CoV-2 progenitor. The first of these viruses reported by WIV, RaTG13
(Zhou P. et al., 2020), is certainly too divergent to be the SARS-CoV-2
progenitor, providing key genetic evidence that weakens the “lab-leak”
notion. Further, three other sarbecoviruses collected in Yunnan
independently of the WIV are now the closest bat coronaviruses to SARS-
CoV-2 that have been identified: RmYN02, RpYN06, and PrC31 (Lytras
S. et al., 2021).
If different routes of transmission to humans are in place, why is
emergence so rare that only two major outbreaks have occurred in the last
two decades? Spillover events are not so unusual in locations where more
frequent human-animal contacts take place. This is indicated by serology
studies showing evidence for SARSr-CoV–specific antibodies in people
living in rural locations and even higher rates recorded in people living
near bat caves (Lytras S. et al., 2021). Spillover risk will increase with
human encroachment into rural areas, resulting from new travel networks
around and between urban areas. When a novel virus is then exposed to a
densely packed human population, such as in Wuhan city, these spillover
events have a much higher chance of resulting in substantial onward
spread (Lytras S. et al., 2021).
There are controversial reports that SARS Cov-2 cases in china were
traced with imported frozen foods. The emergence of SARS-CoV-2 has
properties that are consistent with a natural spillover. Although carriage
Clinical Research and Studies Page 3 of 9
from a bat cave of a sarbecovirus close enough to SARS-CoV-2 to be the
progenitor as a research sample to the WIV is theoretically possible, such
a scenario would be extremely unlikely relative to the scale of human-
susceptible animal contacts routinely taking place in animal trading.
Alternatively, bat guano (feces) is collected for use as fertilizer, again on
a much larger scale than irregular research visits to bat caves, consistent
with rare but ongoing SARSr-CoV transmissions to humans in rural areas
(Lytras S. et al., 2021).
Biology of SARS COV-2
SARS-CoV-2 belongs to the virus order Nidovirales, family
Coronaviridae, genus Betacoronavirus (enveloped, positive-sense,
singlestranded RNA viruses that are zoonotic) and subgenus Sarbecovirus
(WHO, 2020). Transmission in human is primarily through direct contact
as well as indirect contact with contaminated objects and respiratory
droplet (WHO, 2020). Its incubation period varies from 5 to 6 days and
ranges 1-14 days. The disease manifests as a flu-like (respiratory) illness
characterized by fever, chills, sore throat, dry cough, expectoration,
dyspnoea, fatigue, headache, myalgia or arthralgia, and less commonly
hemoptysis, conjunctival congestion and gastrointestinal tract
involvement i.e. nausea or vomiting and diarrhoea (WHO, 2020).
The genome of SARS-CoV-2 is similar to that of other coronaviruses and
has four genes that encode the following structural proteins – the S
(spike), E (envelope), M (membrane), and N (nucleocapsid) proteins (Fig.
1). The N protein encapsulates the RNA genome (GenBank accession
number: MN908947) that measures 29 903 nt in length while the other
proteins (the S, E, and M) together comprise the viral envelope (Wu et al.,
2021).
Figure 2. Structural features and its main structural proteins
Studies show that Cold temperatures favor the survival of cold viruses and
reduce immunity in humans and animals by altering the cellular and
molecular defenses against pathogens in the upper respiratory tract
(Shephard, 1998). On the other hand, reports show, the skewed
distribution of COVID-19 mortalities in Italy was not due to the colder
weather of the north alone but likely, an interplay of factors including
“demographics and health, societal customs and epidemic-specific
attitudes, environmental factors and administrative issues” (Goumenou et
al., 2020).
Host Genetic Factors in Coronavirus Susceptibility
The spread of the virus has affected all the regions of the world.
According to the Worldometery report (September 14, 2021), the global
number of cases of COVID-19 has significantly increased, totaling more
than 121,716 new cases, while new deaths have increased to over 2,653.
This brings the cumulative numbers to over 226,214,149 reported cases
and over 4,655,120 deaths globally and in case of Ethiopia 323,715
covid19 cases and 4,967 deaths since the start of the pandemic. The
disease has also contributed significantly to the global disease burden,
creating a devastating effect on the world economy (Ali et al. 2019).
Fever, fatigue, non-productive cough, decreased leucocyte counts, and
radiographic evidence of pneumonia that are very similar to the clinical
symptoms of SARS-CoV and MERS-CoV were among the clinical
manifestations of Covid-19 (Li et al., 2020). Based on the observations
so far, the SARS-CoV-2 causes severe symptoms mainly in aged patients,
most especially those with underlying chronic disease conditions. On the
other hand, a report from Radboud University Medical Center, Nijmegen,
Netherlands notifies two different cases of a pair of previously healthy
young brothers with an average age of 26 years from two different
families require admission to an intensive care unit (ICU) in rapid
succession (Caspar et al., 2020). Further different scenario were reported
among health care workers in which they have been severally exposed to
the virus remain healthy uninfected while some become infected and die.
These unfamiliar cases raise further questions on the consideration of
genetic factors and their possible role in compromising the immune
system and generally, viral infections have shown certain inter-individual
clinical variability. The cause for some people get severe and life-
threatening COVID-19, while others are completely asymptomatic or
suffer just mild symptoms is worth digging extensively into, most
especially with the world searching for answers through research for both
therapeutic and prophylactic measures against the virus (Reyfman et al.,
2019). The mortality rates were interestingly different between countries.
Based on a report of statistica, (2020), the highest mortality rate was seen
in European countries such as in the United Kingdom, Italy, and France,
reaching 15%. On the contrary, the lowest rate of death from COVID-19
was reported from several Western and South Asian countries such as
Singapore (0.06%), Qatar (0.1%), and Bahrain (0.27%) and African
countries suchas Rwanda (0.24%) and Uganda (0.42%) (Smatti MK et al.,
2021). Studies on host genetic variability towards susceptibility and
severity of SARS-Cov-2 so far, focused on ACE-2 and transmembrane
protease serine 2 (TMPRSS2). Studies show that TMPRSS2 expression
increases ACE2‐mediated invasion of cells by SARS‐CoV‐2, hence the
hypothesis that ACE2 and TMPRSS2 variants may modulate viral
infectivity in humans, making some individuals more vulnerable than
others, seems reasonable. Further, Furin, TMPRSS4, and lyosomal
cathepsins shown to be relevant for SARS-CoV-2 entry into host cells
(Torre‐Fuentes et al., 2020).
Clinical Research and Studies Page 4 of 9
Pathogenesis of SARS-CoV-2 virus
According to Robert (2020), based on the cells that are likely infected,
COVID-19 can be classified into three phases that correspond to different
clinical stages of the disease. In the initial stage asymptomatic state in 1–
2 days of infection the inhaled virus SARS-CoV-2 likely binds to
epithelial cells in the nasal cavity and starts replicating. Angiotensin-
converting enzyme 2 (ACE2) is the main receptor for both SARS-CoV-1
and 2 (Carter-Timofte et al., 2020). In SARS-CoV-2 infection, cell entry
is assisted by the ACE2, which functions together with transmembrane
serine protease 2 (TMPRSS2). ACE2 is an important enzyme produced
in the renin–angiotensin system (RAS) for a counterbalance action. In the
second stage which is next few days the upper airway and conducting
airway response and the propagated virus migrates down the respiratory
tract along the conducting airways and leads to a more robust innate
immune response being triggered possibly through the activation of divers
Toll-like receptors (TLRs) (Robert, 2020).
At this time, the disease, COVID-19, becomes clinically manifested. The
level of Cys-X-Cys (C-X-C) motif chemokine ligand 10 (CXCL10) and
some other innate response cytokine such as interferon (IFN)-alpha, IFN
gamma, interleukin (IL)-1β, IL-6, IL-12, and tumor necrosis factor
(TNF)-alpha may be predictive of the subsequent clinical course
(Reyfman et al. 2019). Epithelial cells that are infected with the virus are
a major source of both beta and lambda interferon (Carter et al., 2020).
CXCL10 is an interferon responsive gene that has an excellent signal to
the alveolar type II cell response to both SARS-CoV and influenza
(Hancock et al., 2018, Huang et al., 2020). CXCL10 has also been
reported to be useful as a disease marker in SARS (Debnath et al., 2020).
In the final stage, hypoxia and progression to acute respiratory distress
syndrome (ARDS) are usually seen, characterized by cases of
development of pulmonary infiltrates and very severe disease (Robert,
2020).
The major cause of death in most covid-19 patients is acute respiratory
distress syndrome (ARDS). Previous survey of 41 SARS-CoV-2- infected
patients in admission during the outbreak showed that six of them died
from ARDS (Adeboboye et al., 2020). ARDS is majorly experienced as
shortness of breath, and it is a common immune pathological event in
SARS-CoV and MERS-CoV infections (Mehta et al., 2020). The vital
mechanism for the development of ARDS is cytokine storm (Nikolaidis
et al., 2017; Schnabel, 2020). Cytokine storm arises from the release of
large numbers of pro-inflammatory cytokines (Caspar et al., 2020). This
cytokine storm triggers a deleterious attack by the immune system on the
body, which in the case of COVID-19 is on the healthy lung tissues of
patients. Individuals at older ages are particularly at higher risk because
of their diminished immune response and inefficient ability to repair the
damaged epithelium. The elderly also have reduced mucociliary
clearance, and this may allow the virus to spread to the gas exchange units
of the lung more readily (Chen et al., 2020).
Genetic perspective to the determinants of severity of COVID-19
Infections, viral replication, and inflammation is shown to be influenced
by host genes and based on their effect on susceptibility and severity viral
diseases may classified into categories like virus entry receptors, co-
receptors, or receptor-modifying enzymes. Further, Gene polymorphism
can influence viral disease severity (Kenney et al., 2017; Carter et al.,
2020). It has been observed that genetic mutations or defects in different
facets of cellular innate and adaptive immune responses to viral infections
associated with enhanced severity of numerous viral infections. So far
many of the studies carried out were focus on immunity related genes
(Kenney et al., 2017).
A study carried out by Casanova et al. describes the possibility of some
inborn errors of immunity which could be either monogenic (single gene)
or Mendelian, and that previously healthy, young patients with severe
COVID-19 may carry causal genetic variants (Casanova and Abel, 2020).
The production of Interferon has major role in controlling mechanism of
the immune system in clearing the SARSCov-2. In case of IFN dependent
virus control it profoundly impaired during initial infection in patients
with early-onset of pneumonia, whereas those whose condition
deteriorates later could have milder IFN deficiency or genetically
determined excessive inflammation (Casanova and Abel, 2020).
Variation among human leukocyte antigen alleles were also identified as
possible genetic determinant of susceptibility and severity. To identify
potential susceptibility genes among cohorts afflicted with certain
specific clinical manifestations of viral infections GWAS study were used
whole exome sequencing (WES) has been adopted to identify candidate
gene polymorphisms responsible for specific viral disease phenotype
(Kenney et al., 2017; Carter et al., 2020; Casanova and Helen, 2020). A
study carried by Smatti MK et al. (2021) based on 74 SNPs, located in 10
genes: ICAM3, IFN-g, CCL2, CCL5, AHSG, MBL, Furin, TMPRSS2,
IL4, and CD209 and found Qatari genomes revealed significantly lower
AF of risk variants linked to SARS-CoV-2 severity (CCL2, MBL, CCL5,
AHSG, and IL4) compared to that of 1000Genome and/or the EAS
population (up to 25-fold change). Conversely, SNPs in TMPRSS2, IFN-
g, ICAM3, and Furin were more common among Qataris (average 2-fold
change). Inter-population analysis showed that the distribution of risk
alleles among Europeans differs substantially from Africans and EASs.
Remarkably, Africans seem to carry extremely lower frequencies of
SARS-CoV-2 susceptibility alleles, reaching to 32-fold decrease
compared to other populations (Smatti MK et al., 2021). Another study
carried by Li et al. (2021) to reveal genetic determinants of susceptibility
to COVID-19 severity in the Chinese population. They found two loci on
chromosome 11q23.3 and 11q14.2, were significantly associated with the
COVID-19 severity. Understanding such genetic basis of severity to viral
infections could project the world further into genetic diagnosis of
diseases and infections.
Variations of angiotensin-converting enzyme 2 (ACE2) gene as
important gateway for severity of SARS-Cov-2 infection
ACE2 have many physiological roles under its three main function: a
negative regulator of the renin-angiotensin system, facilitator of amino
acid transport, and the severe acute respiratory syndrome-coronavirus
(SARS-CoV) and SARS-CoV-2 receptor. It is mainly expressed in the
lungs, cardiovascular system, gut, kidneys, central nervous system, and
adipose tissue. Recent studies shown that it serves as SARS-CoV-2
receptor, the infective agent responsible for coronavirus disease 2019,
providing a critical link between immunity, inflammation, ACE2, and
cardiovascular disease (Mahmoud et al., 2020).
The dynamics of spatial transmission of COVID-19 may be attributed to
the variations within ACE2 genes. The X-chromosomes have high
number of immune related genes which are responsible for both innate
and adaptive immune responses to infection. The ACE2 gene is located
on the X- chromosome and is found on the locus Xp22.2. It is 41.04 kb
long and contains 18 or 19 exons which exist in two isoforms (Genbank,
NT011757) [8]. Over expression of ACE2 might predispose patients to
varying degree of severity of this infection as a result of its potential
functional variations which have been shown to alter its activities during
transcription (Huang et al., 2020).
Cao et al. (2020) identified genetic variants, which may potentially alter
ACE2 gene expression. Although it is important to note that while there
Clinical Research and Studies Page 5 of 9
is a possibility of genetic involvements in the mutual expression levels of
ACE and ACE2, scientist have also proposed that the possible cause of
these expressions could be based on individual base line health, which
further determines which of the two most important angiotensin is
expressed in the individual, either angiotensin II or angiotensin 1-7 as
seen in the RAS pathway. Young, healthy, and physically fit individual
will tend to express more of angiotensin 1-7 which allows for regulation
of the pathway and cleavage of ACE2 by enzyme sheddase, leading to
less expressions of the ACE2 receptor required for the entry of SAR-CoV-
2, unlike in older individuals who have higher risks of developing
hypertension, diabetes, heart failure etc., which activates the production
of more angiotensin II necessary for higher expression of ACE2.
Pathological alterations of the ACE2 pathway seems to cause an increased
severity of COVID-19 among patients who suffer from hypertension and
diabetes mellitus (DM) as these diseases are both modulated by ACE2
(Debnath et al., 2020)
According to different studies, because of the presence of high ACE2
density in males lung; males are more susceptible to SARS-CoV-2
infection. A study carried out in Asia based on single-cell RNA
sequencing (RNA-seq) analysis indicated that Asian males may have a
higher expression of tissue ACE2 (Marionneau et al., 2005). This could
be due to the presence of ACE2 gene on the X chromosome, with men
having only one allele and two in women. Furthermore, estrogen levels
have been reported to upregulate ACE2 expression and activity. This
creates a double advantage (i.e., two alleles and estrogen upregulation)
which may be responsible for the less severity of COVID-19 in females.
A report by the Chinese Centre for Disease Control and Prevention
(CDCC) showed an overall female mortality of 1.7% of both suspected
cases as well as serologically confirmed cases versus 2.8% in males. In
serologically confirmed cases, there was a more marked difference of
2.8% female as against 4.7% male mortality (Arnold, 2020). Thus, based
on those findings it is noted that the role of ACE2 on the outcome of
Covid-19 (Gemmati et al., 2020). In contrast as tudy carried by
Alteration in the TLR genes and severity of SARS-Cov-2 infection
The innate immune system is the first line of defense against pathogens,
which is initiated by the recognition of pathogen-associated molecular
patterns (PAMPs) and endogenous damage-associated molecular patterns
(DAMPs) by pattern recognition receptors (PRRs). Among all the PRRs
identified, the toll-like receptors (TLRs) are the most ancient class, with
the most extensive spectrum of pathogen recognition (Li et al., 2018). It
has been identified that those genes responsible for the regulation of toll
like receptor play a major role in severity of Covid19 (Debnath et al.,
2020). In a complex interaction of the virus and the immune system, the
innate immune system recognizes the pathogen-associated molecular
patterns (PAMP) expressed by the virus. This causes a ligand-binding
activation of the pattern recognition receptor (PRRs) such as the Toll-like
receptor, which leads to the expression of specific pro-inflammatory
cytokines (Adeboboye et al. (2020). The recognition of viral pathogens
by the innate immune system is mediated by receptors from two classes
of intracellular PRRs: the RLR family and several members of TLRs that
recognize nucleic acids. TLR7 and TLR8 recognize single-stranded RNA,
while TLR3 recognizes double-stranded RNA (Netea et al., 2012).
It has been noted that lung epithelial cells express all known human
TLRs., such as TLR3, TLR7, and TLR8 (Guillot et al., 2005; Ioannidis et
al., 2013; Iqbal et al., 2020). Since TLR7 recognizes the single-stranded
viral RNA, it is therefore possibly implicated in the disease progression
and consequent clearance of SARS-CoV-2 (Iqbal et al., 2020).
Changes in the genes of TLR cause higher degree of severity of the
covid19 among patients. For instance, in the case of the two separate
families described earlier on, when all genes of the first two brothers were
sequenced in search for possible similar cause of increased morbidity,
Caspar et al. (2020) studied the genes that play significant role in the
immune system. This is based on the fact that several of these genes are
located on the X chromosome and with the two patients being male, then
X-chromosomal gene became most suspicious, since women carry two X
chromosomes while men possess a Y chromosome and only one copy of
the X chromosome. In any case where men have a defect in such gene,
there is no second gene that can take over that role, as in women (Caspar
et al., 2020).
The result of this exome study showed mutations in the gene encoding for
the Toll-like receptor 7 (TLR7). A few letters were missing in the genetic
code of the TLR7 genes, and as a result, the code cannot be properly read,
and almost no TLR7 protein was eventually produced. Impairment in the
TLR7 gene could allow the virus to replicate freely since the immune
system did not get a message of viral invasion which could have led to
activation of the immune signaling cascade that would have produced
interferons for the clearance of the SARS-CoV-2 virus (Caspar et al.,
2020).
Genetic variation of human leucocyte antigen (HLA) genes in severity of
SARS-Cov-2 infection human leukocyte antigen locus is a master
regulator of immunity against infections. It potentially seems to be a
crucial agent influencing the susceptibility and severity of COVID-19. It
has been seen that the genetic variability in the three main
histocompatibility complex (MHC) class genes to affect the susceptibility
and severity of several infectious diseases. HLA molecules are encoded
by a series of 21 protein-coding loci which lie among several other genes
and pseudo genes at the 6p21 region of the chromosome 6 of the human
genome (Fig. 3) (Aicia, 2020). These immune systems are serve in
pathogen recognition, and there is variation among individual in this
regard. These variations can influence how well the immune system
recognizes a given pathogen. Their trans-membrane proteins which are
encoded by the classical (A, B, C, DR, DQ, and DP) HLA genes (Fig. 3)
are principally involved in the presentation of small pathogen-derived
peptides to the T cells at the cell surface, which eventually triggers an
immune response [Ciaglia et al., 2020; Aicia, 2020). Hence, HLA alleles
are crucial component of the viral antigen recognition pathway and shown
to result in viral susceptibility and severity (Kenney et al., 2017; Carter et
al., 2020). Lin et al. (2003) carried an experiment in Taiwan epidemic of
SARS-CoV-2, HLA-class I and II allele typing using PCR-SSOP. In this
study 37 probable cases of SARS, with 28 symptomatic fever patients
later excluded as probable SARS, and 101 non-infected health care
workers who were exposed or might have been possibly exposed to
SARS-CoV-19 (18). Further, 190 normal healthy unrealated Taiwanese
were used. The distribution of HLA class I and II alleles in both cases and
control groups were examined for the presence of association to a genetic
susceptibility or resistance to the SARS-CoV-2 infection.
Clinical Research and Studies Page 8 of 8
Figure 3: Schematic view of the HLA gene locus on the human chromosome 6,
The above fig. 3 shows classical HLA class I (most common are HLA-A,
HLA-B, and HLA-C) and class II (DR, DQ, DP, and DM) molecules in
relation to other immune response gene found on the class III region
This finding indicated that HLA-B*4601 and HLAB*5401 as the most
probable elements that may be favoring SARS-CoV-1infection. After
SARS-CoV-2 proteome was successfully sampled and presented by a
diversity of HLA alleles, analysis showed that HLA-B*4601 had the
fewest predicted binding peptides for SARS-CoV-2, which suggests that
people with this allele may be particularly vulnerable or even present
severe conditions to COVID-19 (Nguyen et al., 2020). It was also
discovered that HLA-B*1503 showed the best capacity to present highly
conserved SARS-CoV-2 peptides that are present among all other
common human coronaviruses. This could also suggest a possibility to
enable cross protective T cell-based immunity (Nguyen et al., 2020).
Furthermore, the intracellular antiviral defense by CTLs is also
complimented by CD4 T lymphocytes (TH cells) through class II HLA.
In the humoral immune response, CD4 T lymphocytes augment the
responses of CTL and provide help for the generation of specific antiviral
antibodies (Aicia, 2020; Jenifer et al., 2009). The correct activation of T
helper cells (TH) for the correct production of antibodies by B cells and
seroconversion is critically regulated by HLA class II genes; therefore,
genetic variations for these molecules might constitute a varied humoral
immune response to the clearance of SARS-CoV-2. For a novel pathogen
like the SARS-CoV-2, a protective T cell-driven immune response to such
unpredicted antigen would require the immune system to generate a new
and diverse TCR repertoire (Lucas et al., 2020). However, diversity of
TCR repertoire has been described to decline with aging (Britanova et al.,
2016). Generally, global data shows a relatively low level of mortality
among young patients with COVID-19 (Ciaglia et al., 2020).
With regard to SARS-COV-2 due to its high rate of mutation it could be
another factor of genetic consideration. SNP in HLA gene of individuals
in conjunction with the ACE2 genes and several other toll like receptor
genes may be of notable significance for future research.
Conclusion
The role of host genetics in susceptibility and severity of COVID-19 is
less studied. Earlier research studies have identified specific human gene
variants that affect enhanced susceptibility to viral infections. More
recently is the current pandemic where the SARS-CoV-2 infection has
shown a high degree of person-to-person clinical variability. A wide range
of disease severity occurs in the patients’ experiences, from asymptomatic
cases, mild infections to serious life threatening conditions requiring
admission into the intensive care unit (ICU). Although, it is generally
reported that age and co-morbidities contribute significantly to the
variations in the clinical outcome of the scourge of COVID-19, a
hypothetical question of the possibility of genetic involvement of ACE2,
HLA, and TLR genes such as TLR7 and TLR3 in the susceptibility and
severity of the disease arose when some unique severe outcomes were
seen among young patients with no co-morbidity.
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