Why do men with Covid-19 suffer worse outcomes than women?

The difference between the female and male immune response to COVID-19 infection, and infections in general, is multifactorial. The well-known determiners of the immune response, such as X and Y chromosomes, sex hormones, and microbiota, are functionally interconnected and influence each other in shaping the body’s immunity. In addition, the quality of mitochondria varies between male and female, and is important in the immune response to viruses.

Research and clinical studies indicate that the genetic sex of patients influences the immune response, the course, and prognosis of many common noninfectious and infectious diseases.A similar correlation has also been observed recently in COVID-19-infected patients; the worldwide statistical analyses of COVID-19 cases indicate that the rate of infection and the seriousness of the outcome are much higher and severe in males than in females.The most popular explanation for this phenomenon is “the immunocompetence handicap model” proposing that in males, the testosterone-dependent secondary male sex traits develop at the expense of the immune response.

Sex hormones are known to affect the innate and adaptive immunological response with the androgens being anti-inflammatory, and the estrogens both pro-inflammatory and anti-inflammatory. However, the mechanisms of these sex-related differences are multifactorial and depend on very complex reciprocal interactions between sex chromosome-encoded and regulatory factors, hormones, and microbiota inhabiting the human body.

In the last decade, it became clear that the microorganisms inhabiting the human gastrointestinal tract differ, in the type and abundance of species, between the sexes. This sex-dependent microbiome, called the microgenderome, develops after puberty when the sex hormones kick in and regulates local and systemic inflammation, and response to infection. Recent studies also indicate that the sex-related difference in the immune response may depend on the sexually dimorphic populations of mitochondria.

The microorganisms acquired during birth, and from the environment (air and food) colonize the human body, especially the digestive system. After puberty, the sex hormones influence the abundance and variety of species inhabiting the male and female body; less variety in males than in females. The compounds produced by the microgendorome reciprocally influence the function of innate and adaptive immunity.

X and Y Chromosome Regulation of Immunity

Each person normally has one pair of sex chromosomes in each cell. Females have two X chromosomes, while males have one X and one Y chromosome.

The human chromosome X consists of over 150 million DNA base pairs and contains more than 800 protein-coding genes, which include the highest number of the innate and adaptive immunity-related genes of the whole human genome, and several hundred non-coding genes. This in itself gives females an immune advantage over their male counterparts. Here is the technical bit:

The immune response genes include fraktaline receptor CXCR3 (C-X-C motif chemokine receptor 3) that directs immune cells, including macrophages, movement into inflamed tissues, and organs; the gene for CD80 ligand that binds to the CD40 receptor on antigen-presenting cells, B cells, monocytes/macrophages, and dendritic cells, and through interaction with CD154 transduces signals for T-dependent B-cell activation; and the interleukin-1 receptor-associated kinase 1 (IRAK1) gene.  B cells, T cells and Dendritic cells are all heavily involved in the body’s ability to quickly and effectively respond to SARS-CoV-2.

Studies showed that the absence of, or extensive deletions in one of the X chromosomes, lead to a variety of autoimmune diseases.

The X chromosome contains many immune response-related genes and 10% of all genomic miRNAs that regulate transcription, splicing, and degradation of many genes. It also, through the specification of female identity, directs maternal purging and transmission of mitochondria.

Female cells may contain different versions of the ACE2 receptor, which may have a different affinity to the virus, which will affect the anti-viral immune response.

The male Y chromosome regulates many different immune-response functions, immune cell numbers, and immune cell phenotypes.

For example, the angiotensin-converting enzyme 2 (ACE2), the receptor for β-type coronaviruses SARS-CoV-1 and SARS-CoV-2, is encoded by the ACE2 gene located on the X chromosome. It is possible that some variants of this gene may code for the receptors with different efficiency of recognizing and binding the virus.

Male cells always express a single ACE2 variant because all cells contain an identical X chromosome. In contrast, a female has a heterogenic ACE2 variant.  Thus, in the female, a potentially more efficient form of ACE2 receptor would be present in only half of all cells. This may limit infectibility with SARS-CoV-2 viruses and, to some extent, give females a relative resistance to the infection. It has also been debated if such ACE2 polymorphism may have an impact on hypertension and other diseases.

The human Y (male) chromosome is much smaller than the X chromosome, consist of around 60 million DNA base pairs.

Phylogenetic studies showed that the males with the haplogroup I, which is one of the most popular European lineages of the Y chromosome, have upregulated inflammatory response, downregulated adaptive immunity, and a higher risk of coronary diseases. Y chromosomes influence the number of natural killer T cells, the gene expression pattern in CD4+ T cells, the immune response of macrophages, and the mortality rate following the infection with coxsackievirus, which argues for the strong impact of the Y chromosome on a large variety of immune cells and immune processes.

Studies of Case et al. showed higher susceptibility to influenza A infection, activate pro-inflammatory cytokine expression in T cells, and increase pathogenic immune response in the lungs.


Studies of the past decades  showed that mitochondria not only generate ATP, but are also indispensable regulators of the innate and adaptive immune response, development, and maintenance/survival and activation of the specific phenotypes of immune cells.

Mitochondria can also affect various signaling pathways and transcription in immune cells by changing the ATP level, alternating their metabolic pathways, and releasing the reactive oxygen species and mitochondrial DNA signals.

Mitochondria can switch macrophage phenotype from the proinflammatory (M1) to the anti-inflammatory (M2). In addition, the localization of mitochondria in the proximity of endoplasmic reticulum membranes of the immune cells directly affects their metabolism and immune-related functions.

Also, the outer membrane of mitochondria contains the mitochondrial antiviral signaling (MAVS) protein that is activated by the viral RNA sensor, the retinoic acid-inducible gene I (RIG-I) that senses the presence of viral RNA. MAVS can also act as an antiviral defense mechanism.

In the macrophages infected with RNA viruses, MAVS interacts with the antiviral protein viperin, affecting the level of antiviral compound interferon.

Proper functioning of mitochondrial MAVS response can be especially relevant and significant for COVID-19 infection where the SARS-CoV-2 virus directly infects alveolar macrophages inducing them to switch on the cytokine storm in the lungs.

All these data indicate that the healthy and properly functioning mitochondria are indispensable for the adequacy of the immune response. Thus, it is not surprising that one of the theories explaining the higher infection rate and severity of infections, such as COVID-19, in males relates to the maternal transmission of mitochondria, and substandard quality of mitochondria in the males.

Recently, melatonin was suggested as a potential adjuvant for COVID-19 treatment. Melatonin has positive effects on mitochondrial homeostasis by scavenging toxic oxygen species and nitrogen-based reactants, enhancing anti-oxidative enzymes, facilitating the electron transport chain, limiting electron leakage, free radical generation, and stimulating ATP synthesis.

In light of our hypothesis that the quality of mitochondria may influence COVID-19 infection, the melatonin treatment of COVID-19 patients may be more beneficial for men than women.