Understanding sex differences in the pathophysiology of SARS-CoV-2 infection

By Shanet Susan AlexReviewed by Danielle Ellis, B.Sc.Apr 29 2022

A recent study published in the journal Immunology analyzed whether sex mattered in the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Background

The SARS-CoV-2 pandemic has posed unprecedented global challenges. Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has a complicated interaction with the immune system. Mounting evidence suggests that SARS-CoV-2 infection has sex-specific variations in the immune response.

Although females and males have comparable SARS-CoV-2 infection rates, COVID-19 causes more severe symptoms and higher mortality in males than in females, according to available sex-disaggregated epidemiological data. Existing data depicts that many biological and behavioral risk factors may have a role in the varied immune responses against SARS-CoV-2.

In the present review, the investigators examined the immunological response to SARS-CoV-2 infection in the setting of sex, with a focus on possible biological processes underpinning disparities in clinical outcomes. The authors stated that understanding sex variations in SARS-CoV-2 infection pathophysiology will aid in the creation of appropriate disease management methods.

Sex variations in COVID-19 immunological response

Females and males have varied immune responses towards pathogens, plausibly explaining why SARS-CoV-2 infection causes distinct disease severity and death. The engagement of the immune system with SARS-CoV-2 begins with viral entrance into the human cell, proceeded by virus recognition and stimulation of the innate immunity in the host, which then leads to adaptive immune response activation. Gene expression in immune cells differs depending on sex, with autosomal genes showing the highest variation. The X and Y sex chromosomes have several immune response-linked genes and were also significant in immunoregulation.

SARS-CoV-2 host entry

CoV spikes (S) connect to host angiotensin-converting enzyme 2 (ACE2) receptors on the upper respiratory tract cell surface, facilitating viral-host cell entry. Upon SARS-CoV-2 attachment, the ACE2 receptor's usual function, such as reducing inflammation, was disrupted. This lowered anti-inflammatory response might aggravate tissue damage.

Although the association between sex and ACE2 levels was exceedingly complicated, certain studies have revealed that males had higher ACE2 expression. One theory stated that men have a higher incidence of heart failure and hypertension than women, possibly justifying the elevated ACE2 levels in males. Existing reports also depict that soluble ACE2 (sACE2) levels among females and males were similar up to 12 years. By the age of 15, however, males' sACE2 levels had surpassed those of females. In line with this theory, one study found that females require a low dose of ACE inhibitors than males for optimum therapeutic benefit.

Non-specific immunity

Females have higher adaptive and innate immunity to infections than men, which might explain the lower COVID-19 severity and death in females. Since female sex steroid estrogen boosts toll-like receptor 7 (TLR7) expression, women might exhibit better clearing of early SARS-CoV-2 infection than males. In some cells, TLR7 may also be able to avoid X chromosomal inactivation. Since females harbor two copies of the X chromosome, escaping X-inactivation permits a more robust TLR7 gene expression.

TLR7 was a critical sensor for the type I interferon (IFN) generation in plasmacytoid dendritic cells (pDCs). Women produce more IFN from their pDCs than males, with estrogen regulating this impact. Female pDCs have higher IFN regulatory factor 5 (IRF5) levels, a key transcription factor in IFN signaling, contributing to heightened type I IFN responses. Besides, a study has shown that autoantibodies impeded type I IFN signaling in a subset of critically sick SARS-CoV-2-infected older males.

Studies have shown that interleukin 6 (IL-6) production in females following viral infection was lower, linking to a better prognosis. COVID-19 was an exception to the rule that females with viral infections have higher cytokine responses. SARS-CoV-2-infected males exhibit significant concentrations of innate proinflammatory cytokines such as IL-18 and IL-8. In persons with severe COVID-19, increased plasma proinflammatory cytokines and chemokines were detected, resulting in a cytokine storm. Further, a high level of tumor necrosis factor (TNF) and IL-1 production can cause rapid inflammation and mortality.

Acquired immunity

Females have more robust humoral immunity towards viral infection and vaccination than males, along with heightened autoreactivity. Differential antibody generation between the sexes was explained by several processes, some of which may be facilitated by estrogen. Evidence for the sex-based disparities in T cell responses in SARS-CoV-2 infection has been discovered, similar to humoral responses. Sex influences the formation of regulatory T cells (Tregs), the distribution of lymphocyte subsets, and the quality of T cell responses. Tregs increase during higher estradiol levels and women have a higher CD4/CD8 T cell ratio.

Compared to females, men with COVID-19 have a decreased lymphocyte count, increased serum C-reactive protein (CRP) values, and heightened neutrophil-to-lymphocyte ratios. T cell activation was more robust in elderly ladies with early SARS-CoV-2 infection than males. Men with COVID-19 have a worse prognosis and poor T cell activation during the early stages of the illness, unlike females.

Men's epigenetic pattern of immune cells changes dramatically between 62 to 64 years, resulting in quicker immunosenescence. On the other hand, females show significant epigenetic alterations in immune cells five to six years after men.

Long-standing impacts

The post-COVID syndrome, which encompasses COVID-19 symptoms that continue after recovery from SARS-CoV-2 infection, was linked to the female sex. Fatigue was the most prevalent symptom of the post-COVID syndrome in one research, and it was linked to elevated IL-6 levels and female sex. Dyspnea was more common in men and not linked to higher IL-6 levels. 

Sex-specific autoimmune responses might impact the course of recovery from SARS-CoV-2 infection. According to a study, females harbor a higher total autoantibody (AAB) response following asymptomatic COVID-19. Nevertheless, the breadth and depth of AAB reaction were high in males following at least slightly symptomatic COVID-19.

Sex hormone-androgen

Existing evidence suggests that COVID-19 progression was probably linked to sex hormones. Males have more androgens, such as dihydrotestosterone and testosterone, whereas females have higher progesterone and estrogen. The expression of transmembrane serine protease 2 (TMPRSS2) and androgen receptors can influence SARS-CoV-2 entrance into host cells. TMPRSS2, a testosterone-regulated gene, maybe more strongly expressed in men, possibly indicating why males have more severe COVID-19. 

Many recent trials showed that androgen deprivation therapy (ADT) did not improve SARS-CoV-2 outcomes, including infection risk, hospitalization, intensive care unit (ICU) admission, or death. Another analysis revealed that COVID-19-positive prostate cancer patients had drastic hospitalization and death rates than COVID-19-positive non-prostate genitourinary cancer patients. Antiandrogens inhibited SARS-CoV-2 entrance and TMPRSS2 expression in human lung cells. Of note, antiandrogen clinical trial findings have been inconsistent. COVID-19-infected males' semen samples contained SARS-CoV-2 genetic material, and the TMPRSS2 and ACE2 genes were also found in the testes. Yet, the TMPRSS2 expression in lung tissue did not differ substantially across the sexes.

Androgens also have several immunosuppressive properties. The immunosuppressive properties of testosterone may aid in overcoming the increased inflammatory milieu that leads to severe COVID-19. A recent report showed that men with COVID-19 have low testosterone and high luteinizing hormone (LH) concentrations than healthy people. Furthermore, the serum CRP levels and testosterone/LH ratio illustrates a negative relationship. Another study discovered a link between total testosterone concentrations and COVID-19 severity biochemical markers. Testosterone shortage appears to be linked to prominent proinflammatory cytokines levels, whereas testosterone can lower these cytokines levels.

Estrogens 

Estrogen receptors were found on immune system cells and influenced immune-related gene expression. A negative relationship between estradiol concentrations and SARS-CoV-2 severity exists among hospitalized patients. Furin was regulated by androgens and estrogens, according to published studies.

Estrogen modulated three other components implicated in SARS-CoV-2 host entry: a disintegrin and metalloprotease 17 (ADAM17), ACE2, and TMPRSS2. Estrogen could also block dipeptidyl peptidase 4 (DPP4), preventing another significant SARS-CoV-2 entrance. In addition, estradiol can stimulate adenosine receptors, which might have anti-inflammatory properties. Estrogen regulates many additional mechanisms that lead to increased inflammation in COVID-19.

Estrogen was also involved in the pDCs control, implicated in the antiviral immune response via IFN production. Females generate far more IFN in response to virus infections than males, resulting in higher priming of the acquired immunity. Estrogen can help prevent thrombosis by increasing nitric oxide production and decreasing platelet aggregation. Estrogen may have a therapeutic capacity for COVID-19 management through these distinct methods. Given the importance of estrogen in immunity, there has been a heightened interest in and worry about estrogen-modulating therapies.

Progesterone

Another hormone that may impact SARS-CoV-2 infection disease development is progesterone. Transient subcutaneous progesterone enhanced clinical outcomes in hospitalized hypoxemic SARS-CoV-2-infected males. Progesterone's anti-inflammatory properties may reduce the risk of cytokine storm and hyperinflammation. Progesterone has been demonstrated to improve IFN pathways, boost Treg differentiation, diminish T helper cell 17 (Th17) responses, impair viral endocytic pathways, and stimulate lung repair by increasing amphiregulin.

Sex variance in COVID-19 vaccine immune response

Vaccine effectiveness was influenced by several variables, like age and sex. Studies have indicated that females have higher cell and humoral-mediated immune responses to vaccinations than males. Since women have a higher rate of adverse reactions to vaccinations, the heightened immunological response to immunizations should be weighed against vaccine safety.

According to a Centers for Disease Control and Prevention (CDC) analysis, women received 61% of the 13.8 million doses of SARS-CoV-2 vaccination delivered in the United States (US) from mid-December 2020 to mid-January 2021, while they accounted for 79% of the recorded adverse effects. Moreover, according to a systematic review and meta-analysis, COVID-19 vaccination was more effective in preventing SARS-CoV-2 infection in males than women.

Conclusions

Overall, the study findings showed sex-specific variations exist at multiple phases of SARS-CoV-2 infection, such as viral entry, the non-specific immune response, and the acquired immunity. Sex hormones, like estrogens, progesterone, and androgens, may have a vital role in the immune system's ability to fight the virus. There may be disparities in the vaccination immunological response between males and females. These sex-specific distinctions at the cellular and molecular levels might explain why men and women have different clinical outcomes. 

The authors mentioned that sex should be addressed as a biological component that may impact therapeutic responses in fundamental, clinical, and translational COVID-19 research. Further research on the role of biological sex in SARS-CoV-2 infection might help improve the specificity of COVID-19 preventative/treatment methods and the health/well-being of the population.