Sex-differential COVID-19 responses are mediated by kynurenic acid

There are apparent sex-related differences in COVID-19 phenotypes. Thus, males have a higher risk of severe COVID-19, with 70% and 90% higher odds of hospitalization and death during their hospital stay, respectively. Inflammation is also elevated in moderately sick hospitalized COVID-19 patients, and males experience inflammation differently from females.

Now, a new study by a research team from Yale University, USA, Edith Cowan University, Australia, and the University of Strathclyde, Scotland, and published on the preprint server medRxiv* in September 2020 shows that kynurenic acid is the underlying factor which is responsible for these differences.

At all ages, it is known that females have more robust T cell immunity than males. As age advances, males show weaker T cell responses and correspondingly worse outcomes. This means that the sex-differential COVID-19 outcomes are linked to differences in the immune response.

Metabolism plays a central role in the body’s functioning, including immune responses. Specific metabolites trigger increased glycolysis and fatty acid synthesis within the immune cells, whether innate-like neutrophils and macrophages or adaptive like the T cells.

On the other hand, stimulation of immunity can cause the metabolic pathways within cells to change, causing altered levels of various crucial metabolites, and thus changing the course of the disease. Not only so, when the levels of various metabolites change, the host cell also competes with the virus for available metabolites.

Study: Kynurenic acid underlies sex-specific immune responses to COVID-19. Image Credit: Kateryna Kon / Shutterstock
Study: Kynurenic acid underlies sex-specific immune responses to COVID-19. Image Credit: Kateryna Kon / Shutterstock

Metabolites Correlate with COVID-19

The researchers first took samples of blood from 39 COVID-19 patients at 3-7 days after hospitalization, provided they had not been on high-dose corticosteroids or the IL-6 modulator tocilizumab and had not been immediately admitted to the intensive care unit (ICU). After adjusting for age, sex, and body mass index (BMI), and other comparisons with the control samples taken from uninfected healthcare workers, they found 75 metabolites that showed correlation with COVID-19. Significantly, they found 17 and 10 metabolites to be positively and negatively correlated with the disease.

Sex-Specific Immune Response-Metabolite Correlation

The researchers went on to look for a correlation between the 75 positively identified metabolites from the patients and controls and immune markers, including both cytokines and chemokines, B and T cells, NK cells, monocytes, and macrophages as well as dendritic cells in peripheral blood in the same. There were 36 correlations in the patients. But when the correlations were classified by sex, they found that more metabolites and immune markers were independently associated, indicating a link between the two physiological functions.

Kynurenic Acid

The researchers also found that kynurenic acid (KA), an endogenous ligand of the aryl hydrocarbon receptor (AhR) and a regulator of the immune response, was positively linked to immune markers, especially in males, and negatively linked with the number of T cells, naïve CD8 T cells, and both CD4 and CD8 effector memory T cells, in males.

In females, the only positive correlation was with IL12p40, CCL3, CXCL9, and SCR.

KA and Sex-Differential Immunity

The researchers also found that KA, generated by the tryptophan metabolism pathway, via kynurenine (K). The KA: K ratio in COVID-19 was analyzed to understand the level of KA production. It was found that in males, a high ratio was linked to high IL-6, CCL1, CCL21, TNFα, and other inflammatory and immune cells and cytokines, including CD8 terminally differentiated effector memory (Temra) T cells. However, at such elevated levels, the count of monocytes, naïve T cells, and IL6-expressing CD4 cells, among other markers, was low.

Overall, a high KA: K ratio showed higher T cell activation in females but lower T cell numbers in male COVID-19 patients. While KA was mildly associated with age in females, the ratio was not. Both KA and the KA: K ratio went up with age in males with COVID-19. In the controls, KA went down with age in males, and KA: K declined with age in both sexes.

Many other metabolites that occurred in this pathway were also correlated with immune markers, including indole-3-lactic acid, which was linked to higher IL4-expressing CD4 cells in males but inversely linked to several cytokines and growth factors in females.

Differential KA Expression Found in Healthy People

The researchers also attempted to find out if the differential expression of KA with the immune response was found in healthy people as well, using tissue-specific data on gene expression from the Genotype-Tissue Expression (GTEx) Project. They found that KYAT gene expression is positively correlated with cytokine levels in males, particularly in some tissues like the brain and the colon, which are targets of COVID-19.

Even in this subset, the increased cytokine levels were correlated with higher KYAT gene expression in older males above 60 years of age. Going deeper, they found that AhR activation was most strongly correlated with KYAT3 expression in the male brain and muscle tissue, increasing with advancing age, and also in the colon.

They went one step ahead, looking at only the CYP1B1 AhR target gene that is used to track AhR activation in the brain. This showed a still higher level of KYAT3 expression. Moreover, the expression of this gene goes up with age in both males and females, as expected from the decline in the KA:K ratios in the control group in this study.

Thus, they conclude, “Older males are uniquely sensitive to increases in KA levels, reacting disproportionately with increased levels of inflammatory cytokines, likely as part of a broader AhR activation.”

Sex-Specific KA-COVID-19-Severity Link

The KA level was then analyzed with respect to the severity of the disease. The study shows that KA levels are comparable in both deteriorated and stabilized patients, whether male or female. The KA: K ratio is higher in males who deteriorated but not in females, whether stable or worsening.

The only one of the metabolites that were linked to disease severity was glutamate, which was much higher in stabilized patients compared to those who showed worsening. KA is an antagonist of the glutamate receptor, and at high levels, it could suppress glutamate secretion. CD4 T cells and CD8 T cells were inversely and positively proportional to glutamate levels, respectively, in progressing COVID-19 patients. Glutamate levels were higher in stabilized patients compared to sicker patients.

Immune markers like eotaxin and IL6 are negatively and positively correlated with glutamate levels, respectively, in sicker female patients. In males with a worsening disease, it is negatively correlated with CD4 T cells and with IL-5. In other words, a high ratio of KA:K and a low glutamate level indicates a poor prognosis in males with COVID-19.

Implications

The findings that severe COVID-19 is linked to KA and the KA: K ratio, and to immune responses separately in the sexes, reflects earlier studies. This shows that kynurenine metabolism is related to the differences in immune response between the sexes. Older males are very sensitive to changes in the expression of KYAT genes, and thus to KA levels, which are naturally related to higher tissue cytokine levels. The tissues where these differences are obvious are those which are affected in COVID-19.

KA is a ligand for AhR, activating it. Activated AhR is a master regulator of immune responses and inflammation. Changes in the AhR pathway mediate differential immune response in males, especially since this pathway is inhibited by testosterone, which declines in older males. This perfectly ties in with the increased vulnerability of healthy older males to AhR activation by endogenous compounds. Both type 2 diabetes and obesity are known to increase the risk for COVID-19, as well as to increase AhR ligand activity. When these factors are both present, there is a much higher risk of a cytokine storm as a result of COVID-19 in older males.

Of course, KA and the KA: K ratio may be an underlying mechanism in many other inflammatory syndromes. However, AhR remains a promising potential target for COVID-19 treatment.

This sex-differential activation of AhR is reported for the first time in humans. Moreover, glutamate was the only metabolite found to be associated with disease severity. These aspects need further study to understand their role in COVID-19-related immune response and patient outcomes, especially the differences between males and females. Such research may help to change the course of the disease by altering the levels of these metabolites.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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