Periodic Reporting for period 1 - HybridImmunogenetics (Effects of major histocompatibility complex immunogenetic profiles of wild hybrid and non-hybrid marmosets on their susceptibility to arbovirus infections)
Okres sprawozdawczy: 2019-03-01 do 2021-02-28
In this project, we asked the question ‘How do combinations of different parental genes in hybrid primates (admixed individuals resulting from interbreeding between different species) affect a hybrid individual’s susceptibility to pathogenic disease?’ This project was motivated by an 2016-2019 outbreak of Yellow Fever virus (YFV) in large urban centers of southeastern Brazil, including the cities of São Paulo and Rio de Janeiro. YFV is transmitted to human and non-human primate hosts by mosquitos and human symptoms of YFV infections range from mild flu-like symptoms to severe hemorrhages and liver disease to death. Additionally, this last YFV outbreak in Brazil caused alarming amounts of human and non-human primate infections and deaths. Marmoset species (genus Callithix) are small, charismatic primates found in northeast, central, and southeast Brazil, and frequently interact with humans either as illegal pets or by commonly inhabiting urban areas. Marmoset species hybridize naturally, but as a result of the illegal pet trade, southeast Brazil, also where recent YFV outbreaks occurred, is a hotspot of marmoset primate human-driven (anthropogenic) hybridization. These anthropogenic hybrids live among humans in the highly urbanised areas of southeastern Brazil. Marmosets in general, but especially their hybrids seem relatively tolerant of YFV infections in comparison to other Brazilian primates. This observation motivated this project in using marmosets as models to understand the immunogenetics of hybrid susceptibility to hybrid disease.
Our aims were to specifically focus our study of marmosets on an immunogenetics region called the Major Histocompatibility Complex (MHC) class I. The MHC (in humans called HLA-human leukocyte antigen) essentially determines immune responsiveness and is associated with many diseases due to its enormous genetic variability (multiple alleles) and genomic diversity (differential gene content). Notably, such polymorphisms are associated with susceptibility and resistance to numerous infectious diseases within and across natural populations. The marmoset MHC class I region is made up of three large segments of which we proposed to work with a section called Caja-G/F which is 854,000 bases and contains several “classical” (ie polymorphic) MHC class I genes. In this project, we are applying a set of molecular biology and computational approaches to study the overall MHC class I gene family and other immune genes as well as the virome (full viral host complement) of marmosets.
The proposed work was organized into four scientitific objectives:
Aim 1 – Investigate the genetic diversity of the Caja-G/F segment and Caja-G genes in wild Callithrix.
Aim 2 – Determine how evolutionary forces shape the genetic diversity of the Caja-G/F segment and Caja-G
genes in wild Callithrix hybrids and non-hybrids.
Aim 3 – Reconstruct the evolutionary history of Callithrix species using the Caja-G/F segment.
Aim 4 – Determine the association of Caja-G/F segment haplotypes and Caja-G genotypes with susceptibility to pathogenic disease.
We still maintain these aims, but are also expanding them to several other immunogenetics regions and genes for marmosets.
This work is continuing after the end of the formal MSCA granting period, and final results conclusions for this project will be updated later on. The results of this project will be significant for epidemiology and public health. Mathematical models used to predict disease transmission in both Brazil and Europe would benefit by integration of our results on potential wildlife hosts of viruses transmitted by mosquitos and other insects. As current efforts to control transmission of such viruses mainly center on vector control, data on potential wildlife reservoirs may be useful to update control guidelines of human population exposure to reservoirs. Such guideline updates may carry important implications for transport of viruses via travel between Brazil and Europe and subsequent viral transmission in Europe.
Our aims were to specifically focus our study of marmosets on an immunogenetics region called the Major Histocompatibility Complex (MHC) class I. The MHC (in humans called HLA-human leukocyte antigen) essentially determines immune responsiveness and is associated with many diseases due to its enormous genetic variability (multiple alleles) and genomic diversity (differential gene content). Notably, such polymorphisms are associated with susceptibility and resistance to numerous infectious diseases within and across natural populations. The marmoset MHC class I region is made up of three large segments of which we proposed to work with a section called Caja-G/F which is 854,000 bases and contains several “classical” (ie polymorphic) MHC class I genes. In this project, we are applying a set of molecular biology and computational approaches to study the overall MHC class I gene family and other immune genes as well as the virome (full viral host complement) of marmosets.
The proposed work was organized into four scientitific objectives:
Aim 1 – Investigate the genetic diversity of the Caja-G/F segment and Caja-G genes in wild Callithrix.
Aim 2 – Determine how evolutionary forces shape the genetic diversity of the Caja-G/F segment and Caja-G
genes in wild Callithrix hybrids and non-hybrids.
Aim 3 – Reconstruct the evolutionary history of Callithrix species using the Caja-G/F segment.
Aim 4 – Determine the association of Caja-G/F segment haplotypes and Caja-G genotypes with susceptibility to pathogenic disease.
We still maintain these aims, but are also expanding them to several other immunogenetics regions and genes for marmosets.
This work is continuing after the end of the formal MSCA granting period, and final results conclusions for this project will be updated later on. The results of this project will be significant for epidemiology and public health. Mathematical models used to predict disease transmission in both Brazil and Europe would benefit by integration of our results on potential wildlife hosts of viruses transmitted by mosquitos and other insects. As current efforts to control transmission of such viruses mainly center on vector control, data on potential wildlife reservoirs may be useful to update control guidelines of human population exposure to reservoirs. Such guideline updates may carry important implications for transport of viruses via travel between Brazil and Europe and subsequent viral transmission in Europe.
Due to significant delays faced by this project from the COVID-SARS-19 pandemic, although the MSCA action is officially concluded, work for this project is currently still on-going. We are now sequencing the MHC class I genes and segments in Brazilian marmoset hybrid and non-hybrids using portable long-reading Oxford Nanopore sequencing. We are currently also conducting whole-genome resequencing in marmoset hybrids and non-hybrids which will enable use to look at evolution and genetic diversity of other immune genes in marmosets beyond that of MHC class I. Finally we have also generated virome libraries from over 25 wild Brazilian hybrid and non-hybrid marmosets. Virome data contain information on RNA and DNA viruses that are present within sampled marmosets. We are currently finishing lab work associated with these genomic data and moving into analysis of the generated data. We anticipate completion of this project in 2023. Genomic data will be deposited into public genetic databases, results will be presented at scientific conferences, and submitted for publication in international scientific journals.
The genomic data we are currently producing for this project will represent the most comprehensive genetic information available on marmoset immune genes and their diversity, and we are generating data on immune genes beyond that of what we originally proposed to do. These data will give us unique insights into the role of hybridization in maintaining host health and learn about whether hybrids have an adaptive advantage against viral infections. We are also generating the very first virome data that will be available for wild Brazilian marmosets. During this project, we have trained three female Brazilian students in primatological field work and molecular biology methods. Marmosets are currently emerging biomedical models for human diseases, and genetic information we are generating on marmosets within Brazil will be critical for optimizing use of marmosets in captivity for biomedical purposes.