Loss of chromosome Y (LOY) in low density neutrophils may predispose to severe course of covid-19 in males; consequences of LOY for the immune system

BACKGROUND:

It is unexplained why ~75% of subjects severely ill in covid-19 are males. Published discoveries and our new data, regarding associations between diseases and male-specific risk factor, i.e. mosaic Loss Of chromosome Y (LOY) in leukocytes of aging males, suggests LOY as a possible explanation behind predisposition to a severe course of covid-19. We identified low-density neutrophils (LDNs) as cells that might be a marker of severe disease. LDNs display the highest levels of LOY and are present only in covid-19 patients.

AIMS:

We will perform a comprehensive analysis of the same set of covid-19 patients and controls on three levels: i) DNA for analysis of the level of LOY in blood and selected subtypes of leukocytes; ii) mRNA sequencing and analysis of the impact of LOY on transcriptional profile of leukocytes, in particular LDNs; and iii) analysis of impact of LOY on the levels of proteins in plasma.

WORK PLAN:

We will study four representative groups of patients and controls; i.e. severely affected cases treated at intensive care units, mildly affected cases, very recently convalescent patients and healthy age-matched controls. The latter group is of particular importance as LOY is strongly accumulating with age in adult/aging males.

IMPORTANCE:

We could link a predisposition to a severe covid-19 with a specific mutation in a fraction of leukocytes, in particular LDNs. This might be useful for identifying subjects at risk for severe covid-19 and form the basis for new medical interventions. This could be beneficial for current pandemics and for the future SARS-related viral infections.

It should be stressed that male bias for severe covid-19 infection is consistent with bias for other prior SARS and Middle East respiratory syndrome epidemics (caused by SARS-CoV and MERS-CoV viruses) (PMID: 14742282; 16829999; 25187734). The age-related, male-female differences in covid-19 are also consistent with seasonal influenza A virus infections in Australia and Japan (PMID: 30630435; 21559366).

Thus, this poorly understood bias for susceptibility to viral infections is not specific for covid-19. Testing for LOY in men above 50-years may be helpful to identify still unexposed subjects who may be vulnerable to severe covid-19 and similar future infections. We do not know for how long this pandemic will persist, as new virus variants are appearing.