The Major Histocompatibility Complex and its impact on human and animal health

The Major Histocompatibility Complex (MHC) is a region of the vertebrate genome encoding vital components of the immune system. One of the most diverse gene families within the complex encodes MHC molecules themselves. MHC molecules display fragments of peptides for recognition by T cells, and are thus a cornerstone of adaptive immunity. Understanding the evolution of the MHC will give us a deeper understanding of its biology, with implications for human and animal health.

Connor White is working on two MHC-related questions for his PhD:

1) In humans, MHC molecules are known as Human Leukocyte Antigens (HLAs). Connor is simulating case control studies of HLA protectiveness in the context of multi strain pathogens. This work will help us understand how best to detect whether HLA genotypes are protective against or risk factors for multi-strain diseases. Connor's results have been published in MEEGID: White et al, 2020.

2) Humans possess just one copy of each of three class I MHC loci, but other species possess variable numbers of copies of class I MHC loci. Connor is investigating the evolutionary processes underlying this phenomenon, and their implications for animal health.

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The evolutionary dynamics of human disease resistance

When a mutation that protects against the costs of infectious disease arises in a human population, what factors promote or supress its spread?

Susie Cant’s PhD project addresses this question, taking as case studies:

1) Competition amongst mutations which confer haemoglobin-based resistance to malaria.

2) The possible impact of genetic susceptibility/resistance factors on the mass mortality events which occurred when European invaders made contact with previously isolated populations such as those of the Pacific Islands, bringing with them previously-unknown pathogens. This part of Susie's project is in collaboration with Prof Dennis ShanksLink opens in a new window.

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Autophagy and host-pathogen co-evolution

Living cells accumulate damaged, dangerous or excess material, which needs to be recycled. Autophagy (self-cannibalisation) enables cells to digest such material. Autophagy is especially important for defence against infection, since it allows cells to digest pathogens which have invaded the cytoplasm. We know that agents of infectious diseases can manipulate autophagy in their hosts in order to enhance infection. If we can understand which effector proteins pathogens use to achieve this, we will be able to develop better treatments for infections.

There are so many potential host/pathogen interactions that it is not feasible to use laboratory experimentation to identify all proteins used by pathogens to manipulate autophagy. Mamas Louca's PhD project, co-supervised by Bridget Penman and Ioannis Nezis in the School of Life Sciences, intends to get around this problem using a computational approach exploiting evolutionary theory. Any protein that a host uses to defend against a pathogen, or protein that a pathogen uses to manipulate a host, is subject to the ongoing evolutionary struggle between hosts and pathogens known as "host pathogen co-evolution". Mamas is developing computer simulations of this process for pathogens interacting with the autophagy machinery of their hosts, which he will combine with bioinformatic analyses to help identify which pathogen effectors may be manipulating host autophagy. He is first studying a known manipulator of human autophagy from the influenza A virus. In addition to his theoretical work, Mamas will work with the Nezis lab to verify his theoretical predictions in the laboratory.

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Researchers Involved

Bridget Penman (Assistant Professor, School of Life Sciences)

Connor WhiteLink opens in a new window 
(MathSys PhD student)

Susie CantLink opens in a new window
(MathSys PhD student)

Mamas Louca
(MRC DTP in IBR PhD student)