Kynurenines in the Pathogenesis of Peripheral Neuropathy During Leprosy and COVID-19

Abstract

Inflammatory disorders are associated with the activation of tryptophan (TRYP) catabolism via the kynurenine pathway (KP). Several reports have demonstrated the role of KP in the immunopathophysiology of both leprosy and coronavirus disease 19 (COVID-19). The nervous system can be affected in infections caused by both Mycobacterium leprae and SARS-CoV-2, but the mechanisms involved in the peripheral neural damage induced by these infectious agents are not fully understood. In recent years KP has received greater attention due the importance of kynurenine metabolites in infectious diseases, immune dysfunction and nervous system disorders. In this review, we discuss how modulation of the KP may aid in controlling the damage to peripheral nerves and the effects of KP activation on neural damage during leprosy or COVID-19 individually and we speculate its role during co-infection.

Keywords: COVID-19; kynurenine pathway; leprosy; peripheral neuropathy; tryptophan.

Figure 1

Kynurenine pathway of tryptophan degradation in leprosy and COVID-19. During the course of severe COVID-19 and leprosy immunological reactions there is an increase in production of pro-inflammatory mediators such as TNF, IL-6 and IL-1β that may activate the enzymes that catabolize tryptophan and generate neuroactive kynurenine metabolites that can contribute to peripheral nerve damage and the development of chronic pain. In addition, the cytokine storm that occurs during COVID-19 can also trigger neuropathy and reactional episodes in leprosy patients. The main kynurenine pathway enzymes are shown in red. IDO, indoleamine 2,3-dioxygenase; TDO, tryptophan 2,3-dioxygenase; KATs, kynurenine aminotransferases; KYNU, kynureninase; KMO, kynurenine 3-monooxigenase; 3HAO, 3-hydroxyanthranilic acid dioxygenase; QPRT, quinolinic acid phosphoribosyltransferase; ACMSD, aminocarboxymuconate-semialdehyde decarboxylase; NAD, nicotinamide adenine dinucleotide; CoA, coenzyme A.

Figure 2

SARS-CoV-2 and Mycobacterium leprae infection in peripheral nerve Schwann cells. Peripheral nerves are composed offascicles delimited by the perineurium and enveloped by the epineurium. Inside the nerve fascicles, surrounded by the endoneurium, the axons from each neuron are encircled by Schwann cells (SCs) that form the myelin sheath. SARS-CoV-2 infection activates the transcription factor aryl hydrocarbon receptor (AHR), leading to TNF production. SARS-CoV-2 can also bind TLRs triggering their activation and subsequent production of pro-inflammatory cytokines as IL-6 and IL-1β, cleaved by caspase-1 following inflammasome activation. Recognition of M. leprae via TLRs in the SCs leads to the production of TNF. M. leprae infection in myelinating SCs can also induce apoptotic cell death by a mechanism dependent on TNF and TLR2, degradation of myelin sheath and peripheral nerve fibrosis. TNF (as well as IL-6 and IL-1β) activates the enzyme indoleamine 2,3-dioxygenase (IDO) that catabolizes tryptophan via kynurenine pathway. Formation of neuroactive metabolites of kynurenine (KYN) such as kynurenic acid (KYNA) and picolinic acid (PA) can contribute to nerve damage. SARS-CoV-2 and M. leprae co-infection may trigger a higher pro-inflammatory state leading to increased neuropathy and possibly triggering leprosy reactional episodes.