Lymphotoxin-dependent control of long COVID

SARS-CoV-2 infection causes acute lung pathology and can lead to long-term complications, collectively known as long COVID. These complications include persistent pain, headaches, myalgia, and post-exertional malaise. However, the mechanisms behind these neurological symptoms remain poorly understood. In particular, the role of sensory neurons in the pathogenesis of long COVID is largely unexplored. This knowledge gap hinders the development of novel therapeutic strategies for managing neurological complications associated with long COVID. Animal models are essential for investigating the role of sensory neurons in SARS-CoV-2 infection and testing preclinical interventions. Unfortunately, existing mouse models that allow for the study of SARS-CoV-2 specific effects on sensory neurons in vivo are lacking. In our research, we found that wild-type mice infected with a mouse- adapted SARS-CoV-2 strain develop long-term pain. To further explore the role of sensory neurons in long COVID, we developed a mouse model with selective SARS-CoV-2 infection of sensory neurons through hACE2 expression in Nav1.8+ neurons. Additionally, we identified lymphotoxin beta receptor (LTβR) as a novel immune regulator of chronic pain following SARS-CoV-2 infection. The objective of this proposal is to investigate the role of LTβR signaling in sensory neurons in the pathogenesis of long COVID and to test the potential of LTβR antagonist to mitigate neurological complications of long COVID. Our central hypothesis is that LTβR signaling in sensory neurons promotes long COVID neurological symptoms which can be ameliorated by administration of LTβR antagonist. This hypothesis will be tested through two specific aims. In Aim 1, we will define the impact of LTβR signaling in sensory neurons on long COVID neurological symptoms, viral replication, and immune cell changes in sensory ganglia, using mice with selective LTβR inactivation in Nav1.8+ sensory neurons. In Aim 2, we will assess the therapeutic effects of LTβR antagonist in alleviating long COVID neurological symptoms and identify critical LTβR-dependent pathways in sensory ganglia using single-cell RNA sequencing. This proposal is innovative, significant and impactful, as it will elucidate the role of sensory neurons in long COVID pain, establish new animal models for studying long COVID, and evaluate the therapeutic potential of LTβR antagonists for treating SARS-CoV-2-induced neurological complications.