This is the first installment in a two part series which analyzes biological sex differences in immune responses to SARS-CoV-2 infection. This article focuses primarily on Covid-19 related viral entry as well as innate and adaptive immune responses Covid-19 and their correlation to epidemiological evidence. Part two will highlight the role of sex hormones in SARS-CoV-2 immune responses, examine sex differences in response to several vaccines, and consider their possible therapeutic implications.
Men and women experience Covid-19 differently. Epidemiological studies show that, while males and females have similar infection rates, males are more likely to experience severe Covid-19 and die from SAR-CoV-2 infection. Women tend to have better prognoses; pregnant females are the exception, as they have an increased risk of severe illness, hospitalization, intensive care unit (ICU) admission, mortality and preterm delivery. After excluding societal and behavioral factors, a question remains: what are the biological mechanisms driving these observed differences? Ho et al. attempt to answer this question in their review, The Immune Response to Covid-19: Does sex matter? They consider several biological mechanisms in their work. This article will specifically examine differences in three stages of SARS-CoV-2 immune response: viral entry, activation of host innate immunity, and activation of adaptive immunity.
Sex Differences in SARS-CoV-2 Immune Response
Immune interaction to SARS-CoV-2 entails viral entry, then recognition of the virus and activation of host innate immunity, followed by activation of adaptive immunity. Ho et al. found several potential mechanisms in these three stages which may explain the stronger immune responses seen in females.
In viral entry, SARS-CoV-2 attaches to and enters the host cell by binding to the angiotensin-converting enzyme 2 (ACE2) receptors in upper respiratory tract cells. ACE2 receptors usually decrease inflammation, but the binding alters this function. As a result, ACE2 receptors critically influence SARS-CoV-2 entry to cells and can worsen SARS-CoV-2-caused tissue damage through inflammation.
Ho et al. explain some known sex differences in ACE2 levels which could contribue to in the worse clinical outcomes seen in men. Some studies show that men express higher levels of ACE2, a factor which might increase vulnerability to infection. Males and females have similar soluble ACE2 (sACE2) levels up until 12 years old; after, male sACE2 levels exceed levels found in females. One paper demonstrated that females required a lower dose of ACE inhibitors to achieve optimal therapeutic effect. These data demonstrate potential in targeting ACE2 for Covid-19 treatments and for study on SARS-CoV-2 viral susceptibility, but Ho et al. note that more research is needed to further understand this relationship.
Sex differences were also found when comparing innate immune responses. The initial innate immune response involves viral detection, interferon (IFN) production and inflammasome activation. Innate immune responses are considered crucial to determining disease outcome.
Ho et al. found that females exhibit stronger innate immune responses than their male counterparts. This is seen in sex-specific expression of toll-like receptor 7 (TLR7). Toll-like receptor 7 is important for detecting single RNA viruses such as SARS-CoV-2. It is believed that the more toll-like receptor 7 is expressed, the quicker Covid-19 can be recognized and cleared from the system. Toll-like receptor 7 expression can be upregulated by female sex steroid estrogen. It is also thought to escape X chromosome inactivation in some cells; by evading inactivation, toll-like receptor 7 is therefore expressed more highly in females, who have two copies of the X chromosome.
Interferon (IFN) production involves the creation of proteins called cytokines which aid viral suppression after viral recognition. Chemokines, such as interferons, are a subclass of cytokines which encourage immune cells to move towards a target. Important to note are plasmacytoid dendritic cells (pDCs), immune cells which secrete interferons in response to viral infection.
Women have higher plasma concentrations of IFNα and can produce more IFNα from plasmacytoid dendritic cells (pDCs) than men due to estrogen. They express greater INF regulatory 5 (IFN5), a significant transcription factor in IFN signaling, in their plasmacytoid dendritic cells than males as well. In contrast, one study found that autoantibodies inhibited type I IFN signaling in older males with severe Covid-19.
The last consideration of innate immunity revolves around pro-inflammatory cytokines. Clinical studies associate increased inflammatory cytokine levels with severe Covid-19 pathology. In some cases, elevated cytokine levels lead to a cytokine storm: the flooding of cytokines in the bloodstream that damages tissues and organs.
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 have higher serum levels of IL-8, IL-18 and chemokine ligand 5 (CCL5). A significant correlation exists between high IL-8 levels and reduction in antiviral white blood cells. In comparison, research suggests the lower levels of cytokine levels—interleukin 6 (IL-6) especially—seen in women with Covid-19 are associated with better clinical outcomes; this is unusual, as women typically have stronger cytokine responses than men.
Adaptive immunity is a specialized mechanism which deploys immune cells (lymphocytes) and antibodies to target and destroy pathogens directly. Ho et al. observed sex differences in antibody production, T cell responses and the epigenetic status of immune cells.
Generally, females show higher antibody-mediated immune responses to viral infection and vaccination. This positive effect could be tempered by the greater autoreactivity also noted in this sex. Elevated humoral responses in women could be influenced by several estrogen-mediated mechanisms, including but not limited to germinal center formation, selection against autoreactive B cells, and epigenetic accessibility of B-cell specific loci.
Sex-different T cell interactions seem to impact Covid-19 recovery. Men with Covid-19 have weaker T cell activation during early disease than women; in comparison, elderly women with early Covid-19 have more robust T-cell activation. Weak T cell activation, in conjunction with lower lymphocyte count, higher neutrophil-to-lymphocyte ratio, and greater serum C-reactive protein (CRP) concentrations, could explain the poorer outcomes seen in males with Covid-19. Ho et al. state more research is necessary to understand sex differences in the role of T cells in acute infection, lung injury, and vaccine targets.
Another divergence seen in adaptive immunity is in the epigenetic status of immune cells—in other words, physical changes in immune cell DNA structure which do not impact its genetic sequence. One example of this is aging. Between ages 62 to 64 years, males undergo changes in epigenetic landscape which majorly impact the immune system. There is increased expression of innate proinflammatory genes and decreased expression of adaptive immune system genes. In addition, B cell levels and naïve T cell levels decline faster in older men than in their female counterparts. Women exhibit similar epigenetic changes approximately five to six years later than men. A possible biological mechanism is the overexpression of immune genes on the X chromosome of T cells. This overexpression seems to correlate with incomplete X inactivation—as similarly seen in toll-like receptor 7 expression—and epigenetic modifications.
Current knowledge of immunity suggests that strong innate immune responses likely contribute to the lower disease severity and mortality outcomes associated with females. Elevated levels of toll-like receptor 7 and IFNα, along with decreased levels of interleukin 6, may correlate to better prognoses in women. On the other hand, the worse clinical outcomes observed in men could be explained by their higher levels of ACE2 and epigenetic changes in their immune cells, These mechanisms leave important clues to 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 further our understanding.