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A recent Yale study identified a novel link between a metabolic molecule and sex-specific COVID-19 outcomes. 

This study, a collaboration between the Caroline Johnson Lab and Iwasaki Lab, found a specific metabolic pathway that may serve as an effective predictor of COVID-19 outcomes. This pathway may also explain why men tend to experience poorer outcomes than women in the most severe cases of COVID-19. The article was published as a preprint on medRxiv on Sept. 8, before undergoing the peer review process. 

“It was striking to see that … the male sex could be a risk factor for this disease,” Caroline Johnson, assistant professor of epidemiology in the Department of Environmental Health Sciences at the Yale School of Public Health, wrote in an email to the News. “We developed a collaboration to investigate whether sex-differences in metabolism could underlie the immune responses observed.”

The researchers hoped that uncovering novel findings about how and why COVID-19 manifests differently between individuals — specifically between the sexes — would contribute to the global effort to develop more effective therapies for the disease.    

To determine the effects of metabolism on COVID-19 responses, the scientists measured levels of small chemicals called metabolites in the blood of COVID-19 patients.

“Our lab has had a chance to perform in depth analysis of the covid patients’ blood samples, especially focusing on the sex differences in the immune responses,” Takehiro Takahashi, an associate research scientist in the Iwasaki Lab, wrote in a statement to the News.

Using a technology called metabolomics, the researchers were able to identify all of the metabolites present in a biological sample, such as blood, in an unbiased manner. They then examined how various concentrations of metabolites corresponded to the immune responses of people with COVID-19 and compared these results between the male and female sexes.

They found that one molecule in particular, kynurenic acid, may hold key insights into the differences in immune responses between the two sexes. Kyrnurenic acid binds to a receptor called the aryl hydrocarbon receptor, or AhR, in both men and women, which is an important gatekeeper in activating and the body’s immune response. In males with COVID-19, kynurenic acid was found to be positively correlated with age and inflammatory cytokines — signaling molecules involved in mounting an immune response to infections. The experimenters did not observe this positive correlation in females.

“Kynurenic acid can potentially sustain immune responses,” Johnson wrote. “This metabolite has not been previously implicated in any sex-specific immune responses, but in our study, we observed that it positively correlates with cytokine and chemokine levels in male patients only, and could therefore underlie the poorer clinical outcomes observed.” 

Yuping Cai, one of the lead authors of the study and a former postdoctoral researcher in the Caroline Johnson Lab, said that these discoveries open up a new avenue of potential therapeutic strategies for COVID-19, such as directly targeting the kynurenic acid pathway.  

“As we learn more about the impact of the metabolome on COVID-19 disease course, clinicians may find that modulating metabolite levels … may alter disease trajectory,” Cai wrote in an email to the News.

Cai also mentioned that a limited number of patients were recruited for the study, and that additional studies using a larger cohort of participants would help validate their findings.

Johnson said future research in her lab will target the kynurenic acid pathway to see if blocking AhR activation will lessen the severe immune response of many male patients with severe cases of COVID-19.

According to a Harvard database, 2,156 men and 2,373 women have died from COVID-19 in Connecticut as of Oct. 12.


Sydney Gray | sydney.gray@yale.edu