Men and women experience Covid-19 differently. Epidemiological studies show that while infection rates for males and females are similar, males are more likely to contract severe Covid-19 and die from SAR-CoV-2 infection. Women tend to have better expectations; The exception is pregnant females, as they are more likely to have serious illness, hospitalization, intensive care unit (ICU) admission, death, and premature birth. After excluding societal and behavioral factors, a question remains: What are the biological mechanisms driving these observed differences? He and others. Try to answer this question in their review, The immune response to Covid-19: does sex matter? They consider several biological mechanisms in their action. This article will specifically examine the differences in three phases of the immune response to SARS-CoV-2: viral entry, activation of innate host immunity, and activation of adaptive immunity.
Gender differences in the immune response to SARS-CoV-2
Immune interaction with SARS-CoV-2 entails viral entry, then virus recognition and activation of the innate immunity of the host, followed by activation of adaptive immunity. He and others. She found several potential mechanisms in these three stages that may explain the stronger immune responses observed in females.
Enter the virus
In viral entry, SARS-CoV-2 binds to and enters the host cell by binding to the angiotensin converting enzyme 2 (ACE2) receptor in cells of the upper respiratory tract. ACE2 receptors usually reduce inflammation, but binding alters this function. As a result, ACE2 receptors critically affect SARS-CoV-2 entry into cells and can exacerbate SARS-CoV-2-induced tissue damage through inflammation.
He and others. Explain some of the known gender differences in ACE2 levels that may contribute to the worst clinical outcomes observed in men. Some studies show that men express higher levels of ACE2, a factor that may increase susceptibility to infections. Males and females have similar levels of soluble ACE2 (sACE2) up to the age of 12 years; Thereafter, levels of SACE2 in males exceed levels found in females. One paper showed that females require a lower dose of an ACE inhibitor to achieve the optimal therapeutic effect. These data demonstrate the potential to target ACE2 for therapies of Covid-19 and for the study of SARS-CoV-2 viral susceptibility, but Ho et al. Note that more research is needed to further understand this relationship.
Gender differences were also found when comparing innate immune responses. The primary innate immune response includes viral detection, production of interferon (IFN) and activation of the inflammatory particle. Innate immune responses are critical in determining disease outcome.
He and others. It found that females exhibit stronger innate immune responses than their male counterparts. This is shown in the sex-specific expression of the graph-like receptor 7 (TLR7). Monitor-like receptor 7 is important for the detection of single RNA viruses such as SARS-CoV-2. It is believed that the more receptors similar to the number 7 are expressed, the faster Covid-19 can be identified and removed from the system. Monitor-like receptor 7 expression can be regulated by the female sex hormone estrogen. It is also thought to escape inactivation of the X chromosome in some cells; By avoiding inactivation, the 7-like receptor is more expressed in females, who have two copies of the X chromosome.
Interferon (IFN) production involves the creation of proteins called cytokines that help suppress the virus after the virus has been identified. Chemokines, such as interferon, are a subclass of cytokines that encourage immune cells to move toward a target. It is important to note plasma dendritic cells (pDCs), which are immune cells that secrete interferon in response to viral infection.
Women have higher plasma concentrations of IFNα and can produce IFNα from plasmatic dendritic cells (pDCs) than men due to estrogen. They express a greater INF-regulatory 5 (IFN5), an important transcription factor in IFN signaling, in their plasmacytic dendritic cells compared to males as well. In contrast, one study found that autoantibodies inhibited type 1 interferon signaling in older males with severe COVID-19.
A final consideration of innate immunity revolves around pro-inflammatory cytokines. Clinical studies link increased inflammatory cytokine levels with severe Covid-19 pathology. In some cases, elevated cytokine levels lead to a cellular storm: a flood of cytokines in the bloodstream resulting in tissue and organ damage.
In this regard, males typically have higher levels of innate proinflammatory cytokines such as interleukin-8 (IL-8) and 18 (IL-18) than their female counterparts. They also had higher serum levels of IL-8, IL-18, and chemokine ligand 5 (CCL5). There is a significant association between elevated IL-8 levels and decreased antiviral white blood cells. By comparison, research suggests that lower levels of a cytokine – interleukin-6 (IL-6) in particular – seen in women with Covid-19 are associated with better clinical outcomes. This is unusual, because women usually have stronger cellular responses than men.
Adaptive immunity is a specialized mechanism that deploys immune cells (lymphocytes) and antibodies to directly target and destroy pathogens. He and others. Note the gender differences in antibody production, T-cell responses and the epigenetic status of immune cells.
In general, females show higher immune responses mediated by antibodies to viral infection and vaccination. This positive effect can be mitigated by the greater intrinsic activity also observed in this genus. Elevated humoral responses in women can be influenced by several estrogen-mediated mechanisms, including but not limited to germinal center formation, selection against active B cells, and epigenetic accessibility of specific B cell loci.
Different gender T-cell interactions appear to influence Covid-19 recovery. Men with Covid-19 have weaker T-cell activity during early illness than women; In comparison, older women with early Covid-19 had stronger T-cell activation. Poor T-cell activation, combined with lower lymphocyte counts, higher neutrophil-to-lymphocyte ratio, and increased serum C-reactive protein (CRP) concentrations, could explain the poor outcome seen in males with Covid-19. He and others. stated that further research is necessary to understand gender differences in the role of T cells in acute infection and lung injury and for vaccine targets.
Another difference seen in adaptive immunity is in the epigenetic state of immune cells – in other words, physical changes in the DNA structure of immune cells that do not affect their genetic sequence. One example of this is aging. Between the ages of 62 to 64 years, males undergo changes in the epigenetic landscape that significantly affect the immune system. There is increased expression of innate proinflammatory genes and decreased expression of genes of the adaptive immune system. In addition, B-cell levels and naive T-cell levels decline faster in older men than in their female counterparts. Women show similar genetic changes about five to six years later than men. One possible biological mechanism is the overexpression of immune genes on the X chromosome of T cells. This overexpression appears to be associated with incomplete X inactivation—as seen similarly in Toll-like receptor expression—and epigenetic alterations.
Current knowledge of immunology indicates that robust innate immune responses likely contribute to reduced disease severity and female-related mortality. Elevated levels of toll-like receptor 7 and IFNα, along with decreased levels of interleukin-6, may be associated with improved prognosis in women. On the other hand, the worse clinical outcomes observed in men may be explained by their higher levels of ACE2 and epigenetic changes in their immune cells, these mechanisms leave important clues for understanding the relationship between biological sex and immune responses to SARS-CoV-2 infection, but these associations are not linear . More research is needed to advance our understanding.