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

The National Institute of Allergy and Infectious Diseases awarded The University of Texas Health Science Center at San Antonio $234,715 on February 13, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate lymphotoxin beta receptor signaling in sensory neurons and its role in long COVID neurological complications.

The research addresses the mechanistic gap in understanding how sensory neurons contribute to persistent pain, headaches, myalgia, and post-exertional malaise following SARS-CoV-2 infection. The recipient will develop and deploy transgenic mouse models with selective SARS-CoV-2 infection of sensory neurons through hACE2 expression in Nav1.8+ neurons and test lymphotoxin receptor antagonist as a potential therapeutic intervention. The work comprises two specific aims: defining the impact of lymphotoxin receptor signaling in sensory neurons on long COVID neurological symptoms, viral replication, and immune cell changes in sensory ganglia using mice with selective lymphotoxin receptor inactivation in Nav1.8+ sensory neurons, and testing lymphotoxin receptor antagonist administration to mitigate neurological complications.

Performance takes place in San Antonio, Texas with a period of performance ending January 31, 2028. The award funds basic research and preclinical modeling in infectious disease, consistent with the program's mission to support innovative research addressing emerging health challenges.

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.