Immunogenomics of susceptibility to tuberculosis (TB) among nonhuman primate species

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Tuberculosis (TB) is a respiratory disease that causes the death of 1.5 million people each year. Approximately 30% of the human population worldwide are latently infected with TB, creating a risk for developing active TB and transmission. Genomic studies have attempted to identify innate immune genes and polymorphisms that affect susceptibility to TB among humans. Despite findings that suggest correlation of certain genetic polymorphisms in specific immune genes with TB susceptibility, genomic studies have failed to identify specific isoforms that might influence human TB susceptibility. This is because innate immune genes are highly conserved among humans, making them exhibit similar immune responses to TB bacteria. By contrast, different species of nonhuman primates exhibit different levels of susceptibility to TB. Rhesus macaques (macaca mulatta) are more susceptible to TB compared to cynomolgus macaques (macaca fascicularis), yet the underlying mechanism of this variation is unknown. It is crucial to compare innate immune response genes across primate species in response to TB infection to identify the differences in immune orthologs that help eliminate TB bacteria. Using comparative genomics approaches, this study explores and characterizes immune responses across species by ex-vivo infection of different primate blood cells with TB bacteria using long-read RNA-Seq. The use of long-read RNA-Seq provides a more comprehensive annotation of innate immune orthologs across primate species which wasn’t possible in past studies using short-read RNA-seq. This study will help identify species-specific immune orthologs important in immunity against TB, which might ultimately be used to evaluate drug targets for human TB prevention and treatment. This comparative genomic approach can also be applied to identify species-specific immune orthologs as drug targets for other infectious diseases.