Answers in Alanine?

With viral illnesses on the rise globally, it’s clear that we need diagnostic options. But, in many cases, just knowing the name of the causative pathogen is not enough; we need to know how likely a patient is to develop severe disease – and what treatment options exist when it happens.

D-amino acids, uncommon stereoisomers of the more abundant L-configurations, are known to modulate colonization and host defense in bacterial infections (1) and have even been used as a bacterial biosensor (2) – so a group of researchers in Japan opted to explore D-amino acids’ potential in viral infections (3). They noted significantly reduced levels of D-amino acids in the blood of mice with severe influenza A infection, then performed the same testing in human patients with severe COVID-19 requiring respiratory support. These patients exhibited the same reduction in circulating D-amino acids – particularly D-alanine – compared with healthy controls. From this, the researchers concluded that blood levels of D-alanine, and potentially other D-amino acids, may serve as a useful biomarker of disease severity in viral infections.

Because reduced D-amino acids were common in severe disease, the researchers next opted to investigate whether supplementation could alleviate the severity of the infection. Initially, they provided influenza A-infected mice with either D-alanine or D-serine supplementation orally, finding that the D-alanine-supplemented mice exhibited better weight loss mitigation. Analysis of blood and lung samples at five days post-infection further revealed that viral titers were lower in the lungs of mice treated with D-alanine and that tissue damage – such as obstructive alveolar spaces, hemorrhage, and immune cell infiltration – was less prominent.

A mouse model of SARS-CoV-2 infection was then also treated with D-alanine via intraperitoneal injection. In these mice, D-alanine treatment mitigated weight loss and improved survival rates (though survival effects were limited due to the variable efficacy of D-alanine supplementation). Mice whose blood D-alanine levels increased with supplementation exhibited a better overall prognosis.

The researchers hope that their studies will allow healthcare professionals to use circulating D-alanine levels to stratify patients according to their risk of severe disease – and perhaps even alleviate the severity of disease by supplementing patients with reduced blood D-alanine. Before that can happen, though, they highlight the need for further studies in larger human patient cohorts – and potentially on those infected with emerging SARS-CoV-2 variants.