Peptide presentation by bat MHC class I provides new insight into the antiviral immunity of bats

Abstract

Bats harbor many zoonotic viruses, including highly pathogenic viruses of humans and other mammals, but they are typically asymptomatic in bats. To further understand the antiviral immunity of bats, we screened and identified a series of bat major histocompatibility complex (MHC) I Ptal-N*01:01–binding peptides derived from four different bat-borne viruses, i.e., Hendra virus (HeV), Ebola virus (EBOV), Middle East respiratory syndrome coronavirus (MERS-CoV), and H17N10 influenza-like virus. The structures of Ptal-N*01:01 display unusual peptide presentation features in that the bat-specific 3–amino acid (aa) insertion enables the tight “surface anchoring” of the P1-Asp in pocket A of bat MHC I. As the classical primary anchoring positions, the B and F pockets of Ptal-N*01:01 also show unconventional conformations, which contribute to unusual peptide motifs and distinct peptide presentation. Notably, the features of bat MHC I may be shared by MHC I from various marsupials. Our study sheds light on bat adaptive immunity and may benefit future vaccine development against bat-borne viruses of high impact on humans.

Antigenic variation of SARS-CoV-2 in response to immune pressure

“…Different mammals have diverse MHC gene repertoires and thus present distinct antigens. In particular, recent data from various bat species indicated that many MHC class I molecules have a 3-or 5-amino acid insertion in the peptide binding pocket, resulting in very different presented peptide repertoires compared to the MHC class I molecules of other mammals (Abduriyim et al, 2019;Lu, Dan AND Liu, 13 Kefang AND Zhang, Di AND Yue, Can AND Lu, Qiong AND Cheng, Hao AND Wang, Liang AND Chai, Yan AND Qi, Jianxun AND Wang, Lin-Fa AND Gao, George F. AND Liu,William J., 2019;Ng et al, 2016;Papenfuss et al, 2012;Wynne et al, 2016) . Thus, the selective pressure acting on T cell epitopes is most likely volatile and not conserved in humans and bats.…”

“…In fact, all these viruses, with the exclusion of SARS-CoV, were sampled from bats. Thus, whereas structural/functional constraints are expected to be maintained across long evolutionary time frames, the pressure exerted by the human cell-mediated immune response is not, as, in different species, antigen processing within host cells results in the preferential presentation of diverse viral epitopes to T lymphocytes depending on the MHC gene repertoire and on distinct preferences of the antigen processing pathway (Abduriyim et al, 2019;Burgevin et al, 2008;Hammer et al, 2007; Lu, Dan AND Liu, Kefang AND Zhang, Di AND Yue, Can AND Lu, Qiong AND Cheng, Hao AND Wang, Liang AND Chai, Yan AND Qi, Jianxun AND Wang, Lin-Fa AND Gao, George F. AND Liu,William J., 2019;Wynne et al, 2016). Conversely, epitopes for antibodies tend to be conserved across species (Tse et al, 2017;Wiehe et al, 2014) and consequently the selective pressure acting on these positions is expected to be constant across time and hosts.…”

Passage of transmissible cancers in the Tasmanian devil is due to a dominant, shared peptide motif and a limited repertoire of MHC-I allotypes

“…devil MHC-I allele SahaI*27 against the recently described bat MHC-I structure (Ptal-N*01-01)(15), shows a high level of conservation within the F pocket that is absent in the B pocket and likely explains the different binding properties of the devil MHC-I molecules. Interestingly, analysis of all MHC-I alleles expressed by the tumour and host cell lines predicts a B-pocket preference for only SahaI*27 and SahaI*74/88 (which differ by only one amino acid across the a1 and a2 domains), but a F-pocket prediction for a hydrophobic residue is largely consistent across the alleles.…”

“…In devils, three polymorphic classical MHC-I genes (Saha-UA, -UB and -UC) and three nonclassical genes (Saha-UD, -UK and -UM) have been identified, however very little is known about their function or the nature of their ligands (14). Indeed, outside of well characterised species such as human and mouse and those of agricultural importance there has been little analysis of MHC peptide binding in wild species (with a notable exception of the bat MHC (15)(16)(17)). DFT1 cells express low levels of MHC-I, explaining the lack of rejection by CD8 + -T cells (18).…”

“…Interestingly, while the F pocket of SahaI*32(UD) supports the presence of a hydrophobic anchor at pΩ this was not be predicted for SahaI*UK suggesting this non-classical molecule might have not contributed to the immunopeptidome. Indeed, whilst SahaI*32(UD) was found to be present at high levels in the heavy chain fraction analysis, SahaI*UK was present at very low level only in Fibroblasts (figure 1) 15.…”