Using the collaborative cross to elucidate genetic and immune factors mediating chikungunya virus neuropathogenesis - the alphavirus chikungunya virus (CHIKV) represents a RE-emerging public health…

The National Institute of Allergy and Infectious Diseases awarded Texas Biomedical Research Institute (doing business as Southwest Foundation for Biomedical Research) $962,661 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to develop immunocompetent mouse models of chikungunya virus-induced neurological disease.

The project, which runs through August 31, 2031, uses the genetically diverse Collaborative Cross mouse population to elucidate genetic and immune factors mediating chikungunya virus neuropathogenesis. Chikungunya virus represents a re-emerging public health threat as mosquito vectors spread to new territories; over 3.7 million cases have been reported in the Americas over the last decade, including local transmission in the United States. While chikungunya typically induces arthritogenic disease, up to 25 percent of cases result in neurological disease such as encephalitis and meningitis. Previous chikungunya neuropathogenesis studies have relied on pre-weanling or immunocompromised mice because adult C57BL/6J mice are not susceptible to chikungunya neuroinvasion following subcutaneous inoculation. The funded research will develop neurodevelopmentally appropriate, immunocompetent mouse models that recapitulate chikungunya neuropathogenesis observed in humans and can be used to elucidate the role of the immune response, particularly T cells, in disease pathology. Work is performed in San Antonio, Texas.

Using the collaborative cross to elucidate genetic and immune factors mediating chikungunya virus neuropathogenesis - the alphavirus chikungunya virus (CHIKV) represents a RE-emerging public health concern as mosquito vectors spread to new territories. Over 3.7 million cases of CHIKV infection have been reported in the americas over the last decade, including local transmission cases in the united states. While CHIKV typically induces arthritogenic disease, up to 25% of cases result in neurological disease, such as encephalitis and meningitis. Studies of human clinical cases and mouse models of infection with CHIKV and other alphaviruses suggest that host factors play a role in disease susceptibility, and the immune response, particularly T cells, primarily drives clinical disease and pathology. The limited accessibility and minimally regenerative nature of the central nervous system (CNS) prevent CHIKV neuropathogenesis studies from being performed in humans. This impediment supports the use of animal models, especially when evaluating the immune response to infection. However, most previous CHIKV neuropathogenesis studies have used pre-weanling or immunocompromised mice, as adult C57BL/6J mice are not susceptible to CHIKV neuroinvasion following subcutaneous inoculation, a more natural route of CHIKV infection. The objective of this proposal is to harness the power of the genetically diverse collaborative cross (CC) mouse population to develop urgently needed immunocompetent, neurodevelopmentally appropriate mouse models of CHIKV-induced neurological disease that accurately recapitulate CHIKV neuropathogenesis observed in humans and can be used to elucidate the role of the immune response in disease. The scientific premise of our proposal is based on robust preliminary findings, including differential susceptibility of mouse strains to CHIKV neuroinvasion, mouse and CHIKV-strain-dependent neurovirulence, and neurological disease correlating with infiltration of immune cells into the CNS. Based on our preliminary findings, our central hypothesis is that host genetic factors mediate CHIKV neuroinvasion and neuropathogenesis by altering the host immune response. We will test this hypothesis through two aims: 1) determine the role host genetic variation plays in neurological CHIKV infection and disease by characterizing CC mice that develop CHIKV-induced neurological disease similar to humans and identifying genomic regions driving susceptibility to CHIKV neuroinvasion, and 2) determine the role the immune response plays in CHIKV neuropathogenesis in mouse models and human neurological CHIKV samples using a combination of RNA sequencing, spatial transcriptomics, and digital histopathological analysis. Developing rigorous, translational mouse models that replicate the clinical and pathological features of CHIKV-induced disease in humans will enable our team to study and understand how CHIKV induces neurological disease and neuropathology. These models will help US achieve our long-term goal of developing effective countermeasures against this important human pathogen with pandemic potential.