With the growing amount of coronavirus research accomplished by researchers globally, the value of the novel coronavirus (SARS-CoV-2) across many relevant research fields has been confirmed. According to big data analytics, the degree of coronavirus infection varies among different genders and different age groups.
On March 15th, Liu Wenjun - a pediatric medical researcher at Southwestern Medical University, published a literature investigation entitled “COVID-19 epidemic: Disease Characteristics in Children” in the Journal of Medical Virology, which describes the epidemiological characteristics of children with the novel coronavirus. Targeting a total of 8,866 COVID-19 patients and their corresponding research reports, results of the survey are similar to that of previous studies - majority of the patients were between ages 36 and 65 years old, while merely 14 children under 10 years of age were infected. But in the cases of children, the age distribution is not very concentrated, as the youngest one is diagnosed just 30 hours after being born and the oldest child is 18 years old. In other words, middle and older aged adults are more prone to be infected by SARS-CoV-2, while the infection rate for children is relatively low.
According to the investigation report published by the COVID-19 Response Team of the US Center for Diseases Control and Prevention (CDC) in Morbidity and Mortality Weekly Report (MMWR), “Coronavirus disease 2019 in children- United States, February 12-April 2, 2020,” a total of 149,082 cases with known age is reported from 50 states in the country. Among these cases, 2,572 are children younger than 18 years old, with underlying disease (13%) and hospitalization status (33%). Although most cases of children with COVID-19 are not severe, the symptoms of infants under 1 year old seem to be more serious, which might suggest the correlation of COVID-19 infection severity to the underlying diseases in pediatric patients. From the analysis of data collected in this article, adults (18-64 years old) accounted for the highest percentage of infections, while children are less likely to be infected by SARS-CoV-2. These findings may support the idea that the symptoms of viral infection are lighter without the effects of underlying diseases, which occur less often among children. Furthermore, during the investigation period, almost no gender difference was detected among reported COVID-19 cases in China, while the infection rate of males in the United States was slightly higher than that of females, at 57%.
Susceptibility to SARS-CoV-2 varies among age groups for many reasons. From the perspective of immunology, the immune system of children is not particularly well-developed compared to adults, therefore the possibility of injury caused by excessive immune reactions in children is relatively low. On the other hand, children have a lower probability of underlying diseases, which largely reduces the risk of severe COVID-19 symptoms. As we all know, the ACE2 receptor protein is integral to SARS-CoV-2 infection onset in human hosts, and ACE2 molecule itself plays an important role in the circulatory protection of the vascular system. However, a large number of middle-aged and elderly adults suffer from underlying diseases of cardiovascular metabolisms - such as hypertension, type II diabetes, coronary heart disease, and more - due to poor lifestyles, abnormal diet, etc., which undoubtedly leads to greater difficulties in a body fighting against SARS-CoV-2.
Chinese Center for Disease Control and Prevention (aka China CDC) published a data report in JAMA on April 7th, which summarized the epidemiological characteristics of the COVID-19 outbreak in China. Of the 72,314 cases investigated, 44,672 are diagnosed, and the distribution characteristics of the confirmed COVID-19 cases were as follows: 87% patients are between 30-79 years old, 1% patients are less than 9 years old, just as children at 10-19 years old (1%), and 80 years old or above (3%). In addition, the overall fatality rate is 2.3% - calculated from 44,672 cases with 1,023 deaths. The fatality rates varied for patients with underlying diseases - cardiovascular disease (10.5%), diabetes (5.6%), chronic respiratory diseases (6.3%), hypertension (6.0%), and cancer (5.6%).
According to the survey, the ratio of males to females among the confirmed cases in Wuhan (the provincial capital of Hubei Province) is 0.99: 1, the ratio of Hubei Province is 1.04: 1, and 1.06: 1 for the entire nation (China). The data here suggested that there is no sex tropism with the host itself, but researchers found in the later investigations that the death rate of males infected by SARS-CoV-2 is significantly higher than that of females. So, what are the factors contributing to this gender differential?
The main host receptor of SARS-CoV-2 is ACE2, which is a gene located on the X chromosome. After the initial outbreak of SARS-CoV, Stanley Perlman from the University of Iowa found that male mice exposed to SARS coronavirus are more susceptible to infection than female mice – male mice also exhibited a lower immune response, more severe lung damage, and higher mortality rate. Female mice became more likely to die when blocking estrogen or removing ovaries, while blocking testosterone in male mice had no such effect. From the results of this experiment, estrogen could play a role in mitigating coronavirus infections to some extent. Does this mean that men are more susceptible to SARS-CoV-2 than women? The truth is that for healthy men and women, the invasiveness of the virus is mostly related to the body's immunity. In China, there are more men with lung infections due to smoking than women. In 2017, a survey on gender differences in cardiovascular diseases in Europe published by Christina Magnussen et al. showed that men suffer more cardiovascular diseases than women, which may explain why the proportion of men infected with SARS-CoV-2 in later investigations is higher than that of women. At the same time, comprehensive population testing could help account for potential differences in testing for asymptomatic cases, which can also be used as evidence to support viral infection severity cannot be defined solely from a gender perspective.
On April 8th, The Lancet Respiratory Medicine journal published an article titled “Sex difference and smoking predisposition in patients with COVID-19” by Cai Hua from the Department of Anesthesiology, University of California, Los Angeles. These correlations may be due to different smoking habits across genders, given that the smoking rate is higher among men in China and that the expression levels of ACE2 was increased among Asian smokers compared to Asian non-smokers.
The report named Potential Influence of COVID-19/ACE2 on the Female Reproductive System by Yan Jing et al, published on May 4th describes the distribution of ACE2 in the female reproductive system, interprets the potentially harmful effects of SARS-CoV-2 on female fertility, and provided evidence for the wide expression of ACE2 in the ovary, uterus, vagina, and placenta. ACE2 regulates follicle development and ovulation, corpus luteum angiogenesis and deformation, and influences regular changes in endometrial tissue and embryo development. The above evidence indicates that the viral invasion and infection severity are closely related to the expression and distribution of its host receptors. However, it is not that the virus has gender preference, but only that the health status of the host and its immune response towards the virus varies among gender, resulting in the different phenotypes observed.
Similarly, the mortality rate of SARS-CoV-2 infection for pregnant women is higher than that of non-pregnant women. On March 17th, researchers from the London Institute of Technology in the United Kingdom published an article entitled Coronavirus in pregnancy and delivery: rapid review. The researchers searched Pubmed and MedRxiv for female case reports, observational studies, randomized controlled experiments and related paper data of women infected with SARS-CoV-2 during pregnancy. The investigation found that there were 32 pregnant women affected by SARS-CoV-2, but no vertical transmission was found. On March 17th, the Journal of Reproductive Immunology published a review paper covering Why are pregnant women susceptible to COVID-19? An immunological viewpoint, which also showed there was no direct proof that the virus could be transmitted vertically, but it was found that the incidence of premature delivery in pregnant women increased. From the perspective of analysis, it is believed that SARS-CoV-2 may change the immune response at the maternal-fetal interface to influence maternal and infant health. The immunity of pregnant women is greatly challenged in the face of viral invasion, but the maternal immune system status changes with the growth of the fetus during different gestational periods, rather than maintaining immune suppression. Additionally, high levels of estrogen and progesterone during pregnancy can bring about upper respiratory tract swelling and restrict lung expansion, making pregnant women more susceptible to respiratory pathogens.
From the above discussion, we found that SARS-CoV-2 infection differs in severity and distribution across different ages and genders, but the specific mechanisms contributing to the differences in viral invasion still need further verification and analysis. In exploring the process of human-susceptible viral diseases, mouse models play an important role in revealing how viruses cause pathological changes and related mechanisms such as the body's immune response.
As a professional global provider of genetic modification model animal technical services, Cyagen is working hard to develop models for the three main coronavirus receptors – ACE2, DPP4, and APN - catered to the wide variety of current research needs. We are in the process of creating humanized (endogenous replacement or ROSA26 gene knock-in) and gene knockout (KO) models on C57BL/6 and BALB/c backgrounds to meet the current demand. We aim to provide researchers in the field of biomedical research with an ideal mouse model for the elucidation of SARS-CoV-2 mechanisms of infection and pathogenesis, as well as development of vaccines and antiviral drugs. Learn more about how to order these key models by visiting our COVID-19 One-Stop-Solution.
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