Deciphering host genetics and viral determinants of MPOX epidemiology in the Democratic Republic of Congo (DECIPHER-MPOX)

Background: Monkeypox virus (MPV) is a member of the Poxviridae family that includes smallpox, cowpox and chickenpox viruses. Endemic to equatorial Africa following casual human to animal or human to human transmission , recent events have seen an increased incidence with indications of sexual transmission. The disease is characterized by fever, muscle aches, skin rash, lymphadenopathy, oral sores, sore throat, cough, etc. Within any cluster of high risk contacts of a case mpox; however, not everyone exposed develops clinical disease. Moreover, among those contacts who develop mpox, not everyone gets severe disease or dies. Hypothesis: Host genetic & viral factors explain the differential outcomes following exposure to MPV. Objectives: To determine the host genetic and viral determinants of mpox disease in Kamituga area, South Kivu province, DRC. Specifically, we will (I) establish well phenotyped cohorts of house-hold contacts, (II) determine rare variants via family trios; (III) undertake RNASeq for transcriptomics, and (IV) study differential cellular immunity profiles using digital cell sorting (DCS) , (V) identify viral variants that drive severe disease Methods: Whole exome sequencing (WES), transcriptomics and DCS studies of house-family contacts clinically prequalified by PCR and serological testing. Virus gDNA will be reverse transcribed from sequenced host RNA and characterized by comparative genomics and phylogeny. Potential impact: This project will elucidate host genetic & viral determinants of susceptibility to mpox disease in context of natural exposure and infection; that may serve as correlates of immune protection following vaccination.