The role of Interleukin-4 in COVID-19 associated male infertility – A hypothesis
Authors: Haritha Myakala
Rituraj Chakraborty
Abilash Valsala Gopalakrishnan
Kamalakannan Siva
Mohana Devi Subramaniam
Mahalaxmi Iyer
Geetha Bharathi
Balachandar Vellingiri
Kaviyarasi Renu
Journal: Journal of Reproductive Immunology (2020)
Discipline: IMMUNOLOGY
Keywords: COVID-19; Inflammation; Interleukin-4; JAK-STAT; Male infertility
Affiliations: Department of Biomedical Sciences, School of Biosciences and Technology, VIT, Vellore, Tamil Nadu 632014, India., Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai 600 006, India., Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore 641 043, Tamil Nadu, India., Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India., National Center for Disease Control, Ministry of Health and Family Welfare, Government of India, New Delhi 110054, India., Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India. Electronic address: ., Department of Biomedical Sciences, School of Biosciences and Technology, VIT, Vellore, Tamil Nadu 632014, India. Electronic address: .

Abstract:  COVID-19 is a present-day complex pandemic infection with unpredictable levels of morbidity and mortality in various global populations. COVID-19 is associated with the different comorbidities with its change in biological function such as causing heart dysfunction via deregulating ACE-2 receptor, gastrointestinal risk via causing vomiting, diarrhea, and abdominal pain, chronic kidney disease via proteinuria and hematuria, diabetes mellitus, liver injury via increasing ALT, AST and bilirubin level, lung injury, CNS risk, ocular risk, and cancer risk. In this, we are focused on the COVID-19 connected with male infertility. Some of the studies show that the patients of COVID-19 are associated with impaired spermatogenesis. Impaired spermatogenesis via COVID-19 decreases the level of testosterone by disturbing cytokines such as TNF-α, IL-4, IL-6, and IL-12 and further, attenuates the sperm count. COVID-19 is causing inflammation via TNF-α and interferons. IL-4 plays an eminent role in the activation of the JAK-STAT pathway and leads to the disturbing pro-inflammatory cytokine as well as further cause's male infertility. Th2 activates the IL-4 through IgG and IgE and mediates apoptosis with the triggering of STAT signaling. The activated STAT signaling augments Batf/Irf4, and the Bach2/Batf pathway. On the other hand, SARS-CoV-2 is activating the level of Th2 cells. So, we hypothesized that the augmented Th2 cells would disturb the level of IL-4, JAK-STAT signaling, Batf/Irf4, and Bach2/Batf pathway. The disturbed IL-4 decreases the level of the ACE-2 with the inflammation. This further leads to male infertility in COVID-19 patients. So, in this hypothesis, we focused on the role of IL-4 in COVID-19 patients associated with male infertility via Th2 cells and JAK-STAT signaling. 

Retracted: No

PubPeer comments:
 Authors recommend the following in this hypothesis paper to maintain reproductive health;  The COVID-19 causes not only respiratory-related illnesses but also a multi-organ damage, the reproductive organs are also at risk of this viral infection. Thus a few suggestions or guidelines might help to prevent the infection from causing any severe damage to the reproductive system. The following recommendations will be helpful to overcome the issue: The male patients who are infected with COVID-19 must have a follow-up survey to ensure that there is no colossal damage in their reproductive system. u2022 Considering the absence of information about male richness and the proposal that couples think about holding back to get pregnant, sperm freezing might be helpful - emotionally and biologically - during the COVID-19 pandemic. u2022 Social distancing proposals are still set up, so visiting a specialist s office or clinic to talk about sperm freezing isn t suggested, or maybe conceivable, right now. Mail-in sperm testing and freezing alternatives, similar to the Legacy pack, are a significant choice to save your ripeness from the wellbeing and solace of your own home. * Females who have not yet attained their menopause and have acquired COVID-19 disease must check their ovaries life and quality in their future. u2022 Females who are affected with SARS-CoV-2 infection after their recovery must check their fertility status, menstrual cycle and if planning to become pregnant should try to postpone it till their reports are normal. u2022 Both men and females should get their hormone profiles checked after getting recovered from the SARS-CoV-2 infection to avoid any future complications. u2022 Men recovered from COVID-19 disease must have food rich in sperm production such as high content of zinc, garlic, dark chocolates, walnuts, etc. these foods will enable them to regulate sperm production and quantity naturally. u2022 Similarly, female recovered from COVID-19 disease must have a high intake of food which are rich in antioxidants, vitamin D such as green leafy vegetables, etc. as these kinds of food will enable to regulate their fertility quality and reduce any damage naturally. u2022 Pregnant women must be careful during this pandemic situation and must avoid any unnecessary traveling to prevent from this SARS-CoV-2 infection.  This is not an epidemiological study nor there is no molecular data from the COVID-19 patients. Just a hypothesis and recommendations from the authors. The recommendations are so surprising - for example - females who have not yet attained their menopause and have acquired covid-19 disease must check their ovaries life and quality in their future. Some other recommendations are also similarly interesting. ,