As the coronavirus pandemic continues to evolve, scientists around the world are continuing to attempt to understand the nature of the virus, using the data pouring out of affected countries.
Teams of microbiologists and epidemiologists have, in just a few short months, gone from scrambling to identify the pathogen responsible for a mystery new disease to authoring thousands of research papers each day. Everything from the structure of the virus to the biological and sociological factors that impact the spread and severity of disease are being explored.
As cases increase towards their peak in numerous countries, enough data is becoming available to identify important trends. One of the most surprising to be outlined by epidemiologists is the stark difference between the outcomes of men and women: in nearly every country, men are far more likely to develop severe disease and die after a positive COVID-19 test than women. This data is summarised below. The graph shows the male:female ratios of deaths and cases in the countries that report sex-disaggregated data. The vast majority showed an increased likelihood of death with COVID-19. The size of bubbles represent numbers of cases and hovering over each bubble will give the complete data for that country.
The first at-risk groups were easily identified, based on our understanding of how viruses generally affect people. The elderly, the immunocompromised and those with other chronic diseases, such as heart disease, diabetes and hypertension, were clearly at greater risk than others and have been swiftly isolated to reduce the risk of exposure. It hasn’t been as simple to identify other individuals that may specifically be at risk of severe disease with COVID-19. This was initially difficult because early in the pandemic, there was not enough data to identify significant trends. As caseloads rose, it has become clear that men are dying at a much higher rate than women. In the worst cases, men are three times more likely to die with COVID-19. Unofficial accounts from intensive care units claim that up to 70% of all patients are male.
The data is repeated in so many different settings that it is highly unlikely to be a statistical anomaly.
X marks the spot?
The focus now turns to understanding why this gender imbalance exists. Initial explanations focused on behavioural differences. Are men less compliant with hand-washing guidelines? Men are generally less willing to utilise healthcare services, so it is possible that they are seeking medical help when their disease has already progressed to an advanced stage. It has also been suggested that since men are still more likely to engage with risk factors, such as smoking, their risk of complications will be inherently higher.
There may also be biological factors underpinning this difference. While there are no studies specific to COVID-19, there is some evidence that women are more able to mount immune responses against viral infections than men.
A large body of research has focused on a protein called Toll-Like Receptor 7 (TLR7). TLRs are a group of proteins that are present on the surfaces of the cells that make up one of the first lines of defence against pathogens.
All foreign entities that enter our bodies are subject to surveillance by the immune system, which will identify and clear anything that could cause harm or damage. The so-called ‘innate’ arm of the immune system kicks in as soon as pathogens enter the body. TLRs detect biological proteins and their constituents whose only possible origin can be from microorganisms, such as viruses and bacteria. These pathogenic proteins, referred to as Pathogen Associated Molecular Patterns (PAMPs), are a complimentary shape to the TLRs and fit into them with the specificity of a lock and key. The video below explains the role played by TLR7 in clearing viral infections.
Once the PAMP fits into the TLR, a series of processes are initiated that kick-start the body’s various immune responses to viruses. The PAMP that specifically fits into TLR7 is single stranded RNA. Like humans, viruses have their genetic material stored in a biological molecule. Human cells contain two strands DNA coiled round one another into a double helix, while coronaviruses store their genetic information on just a single strand of RNA. RNA serves the same function as, but is structurally different to, DNA.
TLR7 is thought be important in the body’s clearance of coronavirus, as it specifically recognises the type of genetic material utilised by the virus. The gene for TLR7 is found on the X chromosome. Since women have two copies of the X chromosome, and men have one X and one Y, it is thought that women are able to produce more TLR7 than their male counterparts and hence mount stronger immune responses to viral infections.
Women have already been shown to have less severe outcomes upon HIV and Hepatitis C infection than men, perhaps reflecting an inherently stronger ability to fight these infections.
There is a downside to generating strong immune responses. If the target of the immune response is of human origin, it can lead to autoimmune diseases, in which the immune system attacks its own tissues. It has been estimated that roughly 7% of people are affected by an autoimmune disease and a whopping 78% of these are women. Unfortunately, it seems that a strong immune system also means particularly serious autoimmune issues when the system goes awry. Women are also more likely to experience chronic inflammation, a side-effect of the normal immune response that has been linked to numerous diseases if not properly resolved.
Female hormones have also been suggested to play a role. Both oestrogen and progesterone are thought to play a role in the immune response. Hormones, like other biological messenger molecules, can only work and confer their function by binding to complimentary receptors on the surfaces of target cells. Such receptors are found on the surface of nearly every cell that comprises the immune system, suggesting some form of regulation by hormones.
Why would women have a stronger immune response?
Why would it be advantageous for our species for one sex to have a stronger immune response than the other? The answer lies in another identified strength of the female immune response – the ability to produce antibodies. These proteins are another key part of the immune response, and are responsible for neutralising pathogens and activating other arms of the response. They persevere some time after infection has been resolved and can quickly be mass-produced, preventing reinfection. Detection of virus-specific antibodies can therefore be used as a sign of previous infection, hence the scramble to develop such tests in the current crisis.
Women produce a stronger antibody response because mothers are solely responsible for protecting children both before they are born and in their infancy. Antibodies are transferred through both the placenta and breast milk, ensuring that newborn babies are not susceptible to infections when they are at their most vulnerable. Since an infant’s immune system is not fully functional for the first few months of life, immune cells derived from its mother are crucial.
Looking to the future
The data raises questions about how we continue to respond to the pandemic and how we restore normal activity. If men are indeed more likely to experience severe disease and ultimately die after COVID-19 infection, then should tighter measures remain in place longer for men than women? A phased return to workplaces and public gatherings is the most likely plan to be outlined in coming weeks and this data may put forward another factor to consider when deciding which individuals are able to leave lockdown first. Even if this data does not inform our behaviour during and after the current pandemic, it certainly provides an avenue for further research.
The scientific community is indeed looking to use this phenomenon as an opportunity to understand the exact differences between the immune response of males and females. It is hoped that understanding the nuances of the female response to COVID-19 may contribute to the development of more effective treatments and a potential vaccine.
