Sex differences in immune responses to SARS-CoV-2 that underlie disease outcomes

Takahashi, Takehiro; Wong, Patrick; Ellingson, Mallory K.; Lucas, Carolina; Klein, Jon; Israelow, Benjamin; Silva, Julio; Oh, Ji Eun; Mao, Tianyang; Tokuyama, Maria; Lu, Peiwen; Venkataraman, Arvind; Park, Annsea; Liu, Feimei; Meir, Amit; Sun, Jonathan; Wang, Eric Y.; Wyllie, Anne L.; Vogels, Chantal B.F.; Earnest, Rebecca; Lapidus, Sarah; Ott, Isabel M.; Moore, Adam J.; Casanovas-Massana, Arnau; Cruz, Charles Dela; Fournier, John B.; Odio, Camila D.; Farhadian, Shelli; Grubaugh, Nathan D.; Schulz, Wade L.; Ko, Albert I.; Ring, Aaron M.; Omer, Saad B.; Iwasaki, Akiko

A growing body of evidence indicates sex differences in the clinical outcomes of coronavirus disease 2019 (COVID-19)(1–4). However, whether immune responses against SARS-CoV-2 differ between sexes, and whether such differences explain male susceptibility to COVID-19, is currently unknown. In this study, we examined sex differences in viral loads, SARS-CoV-2-specific antibody titers, plasma cytokines, as well as blood cell phenotyping in COVID-19 patients. By focusing our analysis on patients with mild to moderate disease who had not received immunomodulatory medications, our results revealed that male patients had higher plasma levels of innate immune cytokines and chemokines including IL-8, IL-18, and CCL5, along with more robust induction of non-classical monocytes. In contrast, female patients mounted significantly more robust T cell activation than male patients during SARS-CoV-2 infection, which was sustained in old age. Importantly, we found that a poor T cell response negatively correlated with patients’ age and was predictive of worse disease outcome in male patients, but not in female patients. Conversely, higher innate immune cytokines in female patients associated with worse disease progression, but not in male patients. These findings reveal a possible explanation underlying observed sex biases in COVID-19, and provide important basis for the development of sex-based approach to the treatment and care of men and women with COVID-19.