Biochem. Cell. Arch. Vol. 20, No. 2, pp. 000-000, 2020 www.connectjournals.

com/bca ISSN 0972-5075

GENDER-BIAS SUSCEPTIBILITY OF CORONA VIRUS DISEASE : PEEPING

INTO THE FACTORS RESPONSIBLE AND EMERGING TRENDS FROM
INDIAN PERSPECTIVE
Deepak Jha1, Vandana Sharma2, Varruchi Sharma3, J.K. Sharma1,2, #, Suresh Kumar2 and Anil Kumar Sharma4*
1
Department of Student Welfare, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala - 133 207, India.
2
Department of Physics, MMEC, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala - 133 207, India.
3
Department of Biotechnology, Sri Guru Gobind Singh College, Sector 26, Chandigarh - 160 019, India.
4
Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala - 133 207, India.
*e-mail: anibiotech18@gmail.com. Scopus ID 55693618000; ORCID ID:0000-0002-9768-1644 or #sharmajk.69@gmail.com
(Received 17 May 2020, Revised 26 August 2020, Accepted 12 September 2020)

ABSTRACT : Recent pandemic of corona virus disease caused by a novel coronavirus SARS-CoV-2 in humans is the third
outbreak by this family of viruses, which is reminiscent of the SARS-COV outbreak happened in the year 2003. General
characteristics of the novel coronavirus (SARS-CoV-2) especially in regards to the disease susceptibility amongst males and
females have been focused providing a better understanding of the coronavirus disease (COVID-19) in males, females and
children. A thorough literature search for articles in major databases such as PubMed and Google Scholar etc. has been carried
out. COVID-19 has been known to have varied symptoms ranging from mild flu-like symptoms to acute respiratory distress
syndrome, multiple organ failure and death. Ageing, genetics, comorbidities and many other associated factors may play a
crucial role in predisposing an individual towards COVID-19 disease as there exists chronic inflammation, thrombosis and
immune response impairment due to SARS-CoV-2 providing a therapeutic window. Current study emphasizes upon the role of
gender in morbidity and mortality in patients with COVID-19 with men higher at risk to COVID-19 than women in terms of
mortality despite having the similar prevalence of the disease. The study has been well supported by the data available from the
hot-spots affected states from Indian subcontinent. However, current evidence is not sufficient to conclude on the gender-bias
susceptibility but certainly men have an edge over women in terms of susceptibility towards COVID-19.
Key words : COVID-19, gender-bias, susceptibility, ageing, genetic factors, hormones, X-chromosome.

INTRODUCTION study in China (Wu et al, 2020). However, SARS-CoV-2

Recent COVID-19 pandemic has attracted wider
attention of the global scientific community to delineate
and gain major insight into the etiology, prevention,
treatment and mitigation of the disease. Being an acute
respiratory contagious disease caused by a novel
coronavirus SARS-CoV-2 belonging to coronaviridae
family of positive single strand RNA viruses. The very
first case of mortality due to COVID-19 was reported in
Wuhan, China during the end of December 2019 (Lu et
al, 2020; Rothan and Byrareddy, 2020; Su et al, 2016;
Wrapp et al, 2020). Covid-19 has been enlisted as a third
outbreak of zoonotic coronavirus disease after SARS
and the Middle East respiratory syndrome (MERS)
happened earlier (Zhu et al, 2020).
Majority of the COVID-19 patients (upto 80% ) who
contracted SARS-CoV-2 were reported to exhibit mild
or moderate symptoms just like other viral respiratory
infections as evident from a multicentric cross-sectional
was also reported to have an ability to cause severe
disease among elderly population and individuals with
underlying disease conditions including diabetes, obesity,
and cardiovascular disease (Goyal et al, 2020; Guan et
al, 2020). COVID-19 appears to pose a global threat
particularly to the middle-aged and older individuals,
particularly men. Though, it is anticipated that there is an
equal rate of infection among both men and women, still
researchers have established in majority of their findings
that the mortality rate among men was higher (~2.8
percent), as compared to that of women (~1.7 percent)
(https://www.forbes.com/sites/carmenniethammer/2020/
03/06/do-women-and-men-have-a-coronavirus-risk-gap/
#42dd14d16826). The number of reported cases and ratio
of males and females (as reported on 22nd Aug. 2020)
from four Indian states also reflects the similar kind of
trends (Table 1). Even the male-female Ratios of total
number of cases reported as well as the overall ratio from
the 04 states has been shown in Figs. 1 and 2, respectively.
 Deepak Jha et al
The immune system in females has been seen to be more
exuberant but at the same time, women are reported to
be more susceptible to various autoimmune disorders like
rheumatoid arthritis and lupus in which the immune system
shifts into overdrive and attacks the body’s own organs
and tissues as per Dr. Janine Clayton, director of the
Office of Research on Women’s Health at the National
Institutes of Health (https://www.healthline.com/health-
news/men-more-susceptible-to-serious-covid-19-
illnesses]). The emergence of the gender gap as far as
the morbidity and mortality of COVID-19 patients is
concerned, have been noticed just recently though with
the lack of concrete evidence. However, many possibilities
in regards to genetics, immunological, hormonal, life-style
and behavioral factors, have recently been speculated to
play a pivotal role in determining the distinctness of
responses in males and females.
Genetic susceptibility to coronavirus symptoms
At the immune response in contrary to infections,
men are the weaker sex. In viral infections linked to the
respiratory tract men can have worse outcomes quoted
by Sabra Klein. Also in some of the studies, it has been
observed that the same is due to the female sex hormone
estrogen, which is important in playing a significant role
in maintaining immunity of women, the fact for the matter
is that women carry two X chromosomes containing
immune-related genes, on the other hand men carry only
one (https://www.healthline.com/health-news/men-more-
susceptible-to-serious-covid-19-illnesses). Bwire et al
(2020) emphasized upon the fact that there is higher
expression of angiotensin-converting enzyme-2 (ACE-2
receptor) in males than females (Bwire, 2020).
Angiotensin-converting enzyme-2 (ACE 2) has been
known to be a proved receptor for SARS-CoV-2. In an
in vitro experiment, the positive correlation of ACE2
expression and the infection of SARS-CoV-2 has been
demonstrated. Which means that in an organism where
expression of ACE 2 protein is high has a facilitated
environment for pathogenesis of coronavirus (Li et al,
2007). The single nucleotide polymorphism (SNPs) like
rs758278442 and rs759134032 in the region of protective
variants (K31R and Y83H) of ACE2 gene have been
shown to have relatively higher frequency of mutant alleles
in the Asian population in comparison to the global
average, comprising of populations mostly from European
and American descent. The differences in allelic
frequencies of eQTLs of ACE2 observed in different
populations could account for the diversity of expression
pattern of ACE2 gene in populations. ACE2 gene
variations and their impact on the relative levels of its
splice variants from individuals inhabiting COVID-19
hotspots should be able to provide more insights into the
role of ACE2 gene in the gender-biased susceptibility or
resistance to SARS CoV 2 infection (Debnath et al, 2020).
Aging in susceptibility to coronavirus symptoms
Most of the people in reference to COVID-19
experience mild symptoms, but some of the population
have severe or life-threatening responses to the disease.
Old aged people have high risk, the same is due to their
immune systems become less able to fight off with such
infections (Sharma et al, 2020). Major organs of old aged
people such as heart, lungs, high blood pressure, diabetes
etc. are more susceptible to damage caused by the virus
(Cai et al, 2020). In a case study in China, researchers
revealed that older patients above 65 years of age were
more likely to have a severe SARS-CoV-2 infection with
men developing more severe complications than women.
Moreover, the patient survival was found be significantly
higher than older individuals (Jin, 2020). The same study
also reported that the number of men were 2.4 times
higher than that of women in the deceased patients
category despite both the sexes having the same
susceptibility (Jin, 2020).
Life-style and behavioral factors
Additionally, other life style and behavioral factors
such as higher levels of smoking and drinking among men
compared to women do play a significant part as far as
the morbidity and mortality rates in men are concerned
(Bwire, 2020). In another theory in relation to the gender
concerns tobacco smoking has also have an impact on
the disease infections, In some of the studies it has been
proven that smoking is associated with adverse outcomes
of COVID-19, in statistical analysis it has been shown
that smokers are 1.4 times more symptomatic than that
of the nonsmokers and 2.4 times more expected to be
admitted to the hospital in an intensive care unit, and
needed with the mechanical ventilation or die (Vardavas
and Nikitara, 2020). Studies also report on the responsible
attitude of women towards the Covid-19 pandemic by
taking of preventive measures more responsibly than men.
Immunological factors
There exists gender-based immunological differences
which are driven by sex hormones and X chromosomes.
As per the biological records particularly in reference to
the immune system the central role is played by the
genetic differences among men and women, at the
chromosomal level, the X chromosome contains the most
prevalent number of immune-related genes in the whole
genome. In women, there is double copy of XX genes,
on the other hand in men it is XY (Bianchi et al, 2012).
This difference persists both in innate and adaptive
 Gender-bias susceptibility of corona virus disease
immunity (Sabra L Klein and Katie L Flanagan, 2016).
Immunosuppression is attributed to be due to genetic
reasons for the patients who either have had undergone
with organ transplants, or may be because of other
illnesses, for instance infection with HIV/AIDS, or severe
kidney disease etc. People who are frequently taking a
number of medications are more prone to the disease
and very severe infections, and may end-up with more
severe illnesses (Huang et al, 2020). Another factor is
pregnancy, the pregnant women and the pregnancy
conditions can change how the body copes up with
infections such as influenza. In COVID-19 condition, both
the mother and the fetus growing in the womb can be at
high risk of infection (Control and Prevention, 2012;
Roush et al, 2019).
Children are always more susceptible to all the
infections around, however in reference to COVID 19,
there is no clear evidence showing a lower degree of
expression or function of the SARS-CoV’s receptor
(namely ACE2) in children (Lee et al, 2020). At the time
of birth of a child or during the initial months, maternal
antibodies play a role in protecting a child from infections.
The abundant growth of memory T and B cells helps a
child in preventing the development of disease by
commonly encountered pathogens (Aranburu et al, 2017).
In case of SARS, Ebola and H1N1 epidemics, recovering
plasma containing antibodies from those who have
recovered from viral infections were used for treatment
at the early stage of disease. B cell cloned monoclonal
antibodies from already recovered patients have become
a proved candidate therapeutic (Tian et al, 2020). The
vigilance over the immune system of a child or children
to any novel pathogens, including, SARS-CoV viruses
might be based on several factors. Natural antibodies
produced by innate responses play an important role in
protection. Moreover, a population of memory B-cells
(IgM MBCs) generated independently of the germinal
centres has been reported most abundantly in children
as IgM MBCs may bind to many different unknown
microorganisms (Capolunghi et al, 2013). More so
children have the inherent ability to rapidly produce natural
antibodies. Also in infants and children, most MBCs are
CD27dull making them adaptable to newer antigens
(Carsetti et al, 2020).
Furthermore, genetic variations at individual level may
help in explaining the diverse immune responses to a virus
across a population. Variability at genetic levels in MHC’s
may be effective towards all the illnesses caused by
coronaviruses (COVID-19) (Nguyen et al, 2020a).
Human leukocyte antigen (HLA) alleles have been shown
to have differential viral susceptibility. In a study, HLA
binding affinity of all possible 8-mers to 12-mers from
the SARS-CoV-2 proteome have been checked. Further,
it has been noted that the best probable capacity for
SARS-CoV-2 antigen presentation is unrelated to the
HLA allelic frequency in the population (Nguyen et al,
2020b). Cells infected with SARS-CoV-2 are only visible
to CD8+ T cell after virus proteins have been processed
and presented by MHC class I molecules – and only
then are the CD8+ T cell able to eradicate the infection
(Shiina et al, 2004). While antibodies against the COVID-
19 virus are important to prevent or minimize infection,
CD8+ T cells are responsible for clearing the virus from
the body (Khan et al, 2007; Marsh et al, 2005). Hence,
the identification of peptides being presented by MHC
class I becomes of paramount importance. The designing
of the probable vaccine using MHC class I tetramers
could be quite effective not only for the treatment but
also effective against the cellular immune responses and
monitoring, thus keeping a check on the vaccine induced
cellular immunity. The easYmer (https://eaglebio.com/
product-category/all-products/mhc-tetramers) has
permitted researches to generate tetramers and monitor
immune responses. Portfolio of easYmers already covers
34 HLA allotypes (HLA-A,-B,-C) which is further
supplemented by HLA molecules available for custom
tetramer production, bringing the number of available
allotypes up to 81. Thus, the range of allotypes ensures a
coverage to a 2% frequency in the Caucasian population.
The easYmer reagents can also be used to validate the
binding of predicted epitopes to further stratify the
selection of potential COVID-19 vaccine targets (Eagle).
In another study, the genetic variability across the
three MHC class I Genes (human leukocyte antigen
(HLA) A, B and C) that may affect an individual’s
susceptibility to and severity of COVID-19. Also the study
introduces the relationship among coronavirus sequence
conservation and MHC class I antigen presentation, which
shows that individual HLA, haplotype and full genotype
variability likely influence the capacity to respond to
SARS-CoV-2 infection and it was noted that certain
alleles in particular (e.g. HLA-B*46:01) that could be
associated with more severe infection, as previously
shown with SARS-CoV. Indeed, SARS-CoV and SARS-
CoV-2 peptide presentation pattern was further compared
and there was a high degree of similarity noticed between
the two across HLA types (Nguyen et al, 2020a). In the
current pandemic scenario, it is essential not only to focus
on a few ALA allotypes; rather it is essential to be able
to monitor as many allotypes as possible to ensure a novel
vaccine targeting a broad range of allotypes. Furthermore
use of anti inflammatory agents is increasingly being
 Deepak Jha et al

Fig. 1 : Male-female ratios of total number of cases reported from the 04 Indian states.

Fig. 2 : Overall male-female ratio from the 04 Indian states taken together.

Table 1 : Reported cases and ratio of males and females as reported on 22nd August 2020 from 4 Indian states.
State Total cases Males Females Male Female Source
reported %age %age
Odisha 75537 51365 24172 68.00% 32.00% https://statedashboard.odisha.gov.in, Dated: 22nd Aug. 2020
Telangana 101865 66314 35551 65.10% 34.90% hmfw.ap.gov.in/vovid_19_dailybulletins.aspx Media
Bulletin-Covid 19, Dated: 21/08/2020, 8:00 PM
Tamil Nadu 373410 225418 147963 60.37% 39.62% https://stopcorona.tn.gov.in/daily-bulletin
Dated: 22nd Aug. 2020
Haryana 53290 35150 18129 65.96% 34.04% nhmharyana.gov.in/page.aspx?id=208 Daily Health Bulletin
Dated 22nd Aug. 2020
Total 604102 378247 225815 62.61% 37.39%

envisaged as we know that COVID 19 patients display
markedly elevated plasma levels of IL2, IL7, IL10, GCSF,
IP10, MCP1, MIP1A and TNFá (Herold et al, 2020;
Chaolin Huang et al, 2020; Zhao, 2020). The significantly
higher levels of IL 6 (≥80 pg/mL) were seen to be
correlated with a 22 times greater risk of respiratory
failure in COVID 19 patients as a result of the strong
cytokine storm and inflammation (Chaolin Huang et al,
2020). However, the gender-bias differences between
males and females about the cytokine release are yet to
be sorted out.
 Gender-bias susceptibility of corona virus disease
Other miscellaneous factors
In another study, it has been demonstrated that both
males and females respond in a different way to many
RNA and DNA virus infections, in general the males are
known to generate less robust immune responses (Klein
and Flanagan, 2016). The strong immune response in
females leads to immunopathology resulting in fatal
outcomes. Role of sex hormones in both male and females
have a greater role in viral infections such as testosterone
is known to suppress innate immune responses, while
estrogens have displayed dissimilar functions. The
signaling of estrogen hormone has also been shown to
promote adaptive T cell response in female mice by
increasing neutrophil accumulation (Channappanavar et
al, 2017; Robinson et al, 2014).
In another finding, it has been shown that the
differences based on sexes do exist which may influence
the exposure to COVID-19. The study reported that men
could be more susceptible to the disease than women.
Also WHO mission affirmed that men make up to about
51% of cases (Guan et al, 2020). The pregnant women
are more susceptible to the respiratory pathogens than
non-pregnant women. Still, none of the women under
study developed severe COVID-19 pneumonia, which
could be due to the reason that the immuno-suppression
could actually be beneficial in such circumstances. Wang
et al. found that an extreme immune response called
cytokine storm, a flood of immune cells and the
biochemicals they produce, tears through the lung tissue
(Wang et al, 2020). Thus, reducing injury to the lung could
be a useful method to prevent and improve COVID-19-
infected pneumonia-related cytokine-release syndrome-
like (CRSL) in critically ill pneumonia patients (Wang et
al, 2020).
CONCLUSION AND FUTURE PERSPECTIVE
The concrete studies about the role of gender in
morbidity and mortality in patients with COVID-19 are
still at infancy. Growing evidences though of preliminary
nature reveal that men are at higher risk of morbidity
and mortality when it comes to the COVID19 symptoms.
It is evident that men and women have some
immunological distinctions impacting individuals’ ability
to fight an infection including SARS-2-CoV-2. Several
factors such as higher expression of ACE-2 in men, sex
hormones and other genetic and life-style factors have
been anticipated to predispose men to worst outcomes
of the COVID-19 and even death. Controlled and
randomized studies at a large scale would certainly pave
the way for a logical conclusion as far as gender-bias
differences in COVID-19 patients and vulnerability of
associated symptoms are concerned.
ACKNOWLEDGEMENTS
The authors express sincere thanks to the Maharishi
Markandeshwar (deemed to be University), Mullana,
Ambala, Haryana, India for providing necessary facilities
for writing on pandemic research.
Conflict of interest
The authors have no conflicts of interest to declare.
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