This is the first part of a two-part series on biological sex differences in immune responses to SARS-CoV-2 infection. This article focuses primarily on entry of the Covid-19 virus as well as innate and adaptive immune responses to Covid-19 and their relationship to epidemiological evidence. The second part highlights the role of sex hormones in immune responses to SARS-CoV-2, examines sex differences in response to several vaccines, and examines their potential therapeutic implications.
Men and women experience Covid-19 differently. Epidemiological studies have shown that although infection rates are similar in men and women, men are more likely to contract Covid-19 and die from SAR-CoV-2 infection. Women have a better prognosis; pregnant women are an exception because they have a higher risk of severe illness, hospitalization, intensive care unit (ICU) admission, death, and preterm birth. After excluding social and behavioral factors, the question is: what are the biological mechanisms driving these differences? Ho et al. trying to answer this question in their view, The immune response to Covid-19: does sex matter? They consider several biological mechanisms in their work. This article specifically examines differences in the three stages of the immune response to SARS-CoV-2: viral entry, activation of host innate immunity, and activation of adaptive immunity.
Sex differences in the immune response to SARS-CoV-2
Immune interaction to SARS-CoV-2 requires virus entry, followed by virus recognition and activation of host innate immunity, followed by activation of adaptive immunity. Ho et al. Several potential responses have been identified in these three stages that may explain the stronger immune responses observed in women.
During viral entry, SARS-CoV-2 attaches to and enters a host cell by binding to angiotensin-converting enzyme 2 (ACE2) receptors on cells of the upper respiratory tract. ACE2 receptors normally reduce inflammation, but binding alters this function. As a result, ACE2 receptors strongly influence the entry of SARS-CoV-2 into cells and may exacerbate tissue damage caused by SARS-CoV-2 through inflammation.
Ho et al. Explain the known sex differences in ACE2 levels that may account for the poorer clinical outcomes seen in males. Some studies have shown that men have higher levels of ACE2, a factor that increases vulnerability to infection. Soluble ACE2 (sACE2) levels are similar in males and females up to 12 years of age; later, sACE2 levels in men exceed those in women. One paper showed that women required lower doses of ACE inhibitors to achieve optimal therapeutic effects. These data suggest the potential of targeting ACE2 in the treatment of Covid-19 and for SARS-CoV-2 susceptibility testing, but Ho et al. It should be noted that more research is needed to better understand this relationship.
Sex differences were also found when comparing innate immune responses. The initial innate immune response includes virus recognition, interferon (IFN) production, and inflammasome activation. Innate immune responses are critical in determining disease outcome.
Ho et al. Women have been found to exhibit stronger innate immune responses than men. This is evident in the sex-specific expression of toll-like receptor 7 (TLR7). Toll-like receptor 7 is important for detection of single RNA viruses such as SARS-CoV-2. It is believed that the more toll-like receptor 7 is expressed, the faster Covid-19 is recognized and cleared from the system. Toll-like receptor 7 expression can be regulated by the female sex steroid estrogen. It is also believed to avoid inactivation of the X chromosome in some cells; avoiding inactivation, toll-like receptor 7 is overexpressed in females with two copies of the X chromosome.
Interferon (IFN) production involves the production of proteins called cytokines, which help to suppress the virus after it recognizes the virus. Chemokines, such as interferons, are a subclass of cytokines that stimulate immune cells to migrate to a target. Of note are plasmacytoid dendritic cells (pDCs), immune cells that secrete interferons in response to viral infection.
Women have higher plasma IFNα concentrations and can produce more IFNα from plasmacytoid dendritic cells (pDCs) than men because of estrogen. They express more INF regulator 5 (IFN5), a transcription factor important in IFN signaling, in their plasmacytoid dendritic cells than men. In contrast, one study found that autoantibodies inhibited type I IFN signaling in elderly men with Covid-19.
A recent review of innate immunity revolves around pro-inflammatory cytokines. Clinical studies link increased levels of inflammatory cytokines with severe Covid-19 pathology. In some cases, elevated cytokine levels lead to a cytokine storm: a flood of cytokines into the bloodstream that can damage tissues and organs.
In this regard, men usually have higher innate proinflammatory cytokines than their female counterparts, such as interleukin 8 (IL-8) and 18 (IL-18). They also have high serum levels of IL-8, IL-18 and chemokine ligand 5 (CCL5). There is a significant correlation between high levels of IL-8 and a decrease in antiviral white blood cells. In comparison, studies have shown that lower levels of interleukin 6 (IL-6), a cytokine observed in women with Covid-19, are associated with better clinical outcomes; It is unusual that women usually have stronger cytokine responses than men.
Adaptive immunity is a specialized mechanism by which immune cells (lymphocytes) and antibodies directly target and eliminate pathogens. Ho et al. observed sex differences in antibody production, T-cell responses, and the epigenetic state of immune cells.
In general, women show immune responses through antibodies against viral infection and vaccination. This positive effect may be moderated by the greater autoreactivity observed in this gender as well. High humoral responses in females may be influenced by several estrogen-mediated mechanisms, including, but not limited to, germinal center formation, selection against autoreactive B cells, and epigenetic accessibility of specific B cell loci.
Sexually different T-cell interactions appear to influence recovery from Covid-19. Men with Covid-19 have weaker T-cell activation early in the disease than women; in comparison, older women with early Covid-19 have stronger T-cell activation. Weak T-cell activation, low lymphocyte counts, high neutrophil-to-lymphocyte ratios, and high serum C-reactive protein (CRP) concentrations may explain the poor outcomes observed in men with Covid-19. Ho et al. More research is needed to understand sex differences in the role of T cells in acute infection, lung injury, and vaccine targeting.
Another difference observed in adaptive immunity is the epigenetic state of immune cells, that is, physical changes in the DNA structure of an immune cell that do not affect its genetic sequence. An example of this is aging. Between the ages of 62 and 64, men experience changes in their epigenetic landscape that have profound effects on the immune system. There is increased expression of innate inflammatory genes and decreased expression of adaptive immune system genes. In addition, B-cell levels and naive T-cell levels decline more rapidly in older men than in women. Females exhibit similar epigenetic changes approximately five to six years later than males. A possible biological mechanism is overexpression of immune genes on the X chromosome of T cells. This overexpression appears to be associated with incomplete X inactivation—as seen in expression of the 7-terminal receptor—and epigenetic modifications.
Current knowledge of immunity suggests that strong innate immune responses likely contribute to reduced morbidity and mortality outcomes associated with women. Along with decreased levels of interleukin 6, increased levels of toll-like receptor 7 and IFNα, may be associated with a better prognosis in women. On the other hand, the poor clinical outcomes observed in men are explained by their higher levels of ACE2 and epigenetic changes in immune cells, mechanisms that 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 deepen our understanding.