The evolution of diversity in the face of pathogen challenge forms the very core of immunogenetics. Immunity to infection is driven by multiple host genetic factors and their interaction with pathogen mechanisms that can attempt to overcome or evade immunity. The topic of this special issue is Immunogenetics of infectious disease, and specifically as it relates to humans. With up to 10% of the protein coding genes in the human genome dedicated to defence against infectious pathogens, there is considerable scope for this topic, including and beyond the classical immunogenomic loci. Host immunity is also driven by proteins that may include receptors mediating virus entry, through molecules generating or responding to danger signals, and those that bind pathogens or disrupt their growth. Any of these molecules may evolve diversity to combat divergent and evolving pathogens, and therefore their genetic diversity helps define immune diversity.

In this special issue, Hollox and Louzada review the role of genetic variation of glycophorins and the evidence of their involvement in controlling specific infectious diseases (Hollox and Louzada 2022). Glycophorins are expressed by red blood cells, affecting their surface tension and charge. Genetic variants of glycophorins can underlie certain uncommon blood group antigens, in turn affecting resistance to any pathogens that may use them as entry receptors. One variant of GYPA/B, caused by an exceptionally complex genomic structural variation, results in the Dantu NE blood group, which is common in East Africa. Through increasing RBC surface tension, Dantu NE can offer protection from severe malaria, potentially as effectively as Haemoglobin S. In a story familiar to immunogenetics, the complex genomic structural variations of this rapidly evolving system can create barriers for whole-genome SNP and sequence analyses. Accordingly, the GYPA/GYPB chromosomal regions remain largely uncharted in human disease studies, whilst GYPC is a human-specific isotype. The authors neatly describe these genomic regions, summarise how the challenges in analysing them are met, and review the evidence for natural selection shaping their diversity in response to pathogens.

In addition, as stated by Hollox and Louzada, malaria is a major agent of natural selection for humans who live where the disease is endemic. To combat this significant health burden, the Plasmodium falciparum- targeting RTS,S/AS01 vaccine was designed through worldwide efforts beginning in 1984. After decades of development, a pilot project began across Ghana, Kenya, and Malawi in 2019, resulting thus far in the vaccination of over 1.3 million children. Tukwasibwe and colleagues describe the strategy and implementation regarding the RTS,S/AS01 vaccine across sub-Saharan Africa (Tukwasibwe 2023). However, although this vaccine has great potential, its efficacy has been relatively low, and varies across populations. The authors examine human genomic variations that may contribute to observed differences in the efficacy of RTS,S/AS01, with specific focus on polymorphism in HLA, KIR, cytokines, and FcγR. They also discuss how arming African scientists with the tools to perform complex genomic studies is critical towards understanding and resolving differential responses to vaccination. Their review provides an interesting and encouraging perspective on vaccine production in Africa.

Another significant burden on human health, in Africa as well as elsewhere, is tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb). It is estimated that up to 25% of the global population is latently infected with Mtb, yet only approximately 10% of these individuals develop clinical symptoms. Ndong Sima and colleagues review the evidence from multiple lines of study that susceptibility to infection and disease is influenced by genetic diversity, both of the host and of the mycobacterium (Ndong Sima et al. 2022). The authors discuss the advantages and pitfalls of the methods for assessing the heritability of disease, including family, association, PRS, and animal model studies, and synthesise the results that have been consistent across them. A theme common to many of these analyses, and applicable to all large-scale human studies, is the lack of ascertainment and the hidden population structure of underrepresented populations, especially Africans. The authors describe their own and others’ efforts to overcome these obstacles specifically regarding TB susceptibility. They discuss how these studies will aid in the prevention and treatment of TB worldwide.

Characterised by reciprocal genomic mutations, the long-term coevolution between herpesviruses and their host provides some of the best-characterised examples of host adaptation and immune evasion strategies. Palmer and Norman discuss the co-evolution of humans with herpesviruses and the impact of HLA and NK cell receptor variation on infection and its course (Palmer and Norman 2023). Genetic associations across the eight human herpesviruses are analysed, and HLA alleles that are associated with diverse herpesvirus-related phenotypes are identified. Similarities and differences in these associations across human population groups are discussed, as are the underlying mechanisms. Although multiple distinct allotypes differentially associate with specific herpesvirus infections, broadly protective (HLA-A*02) and susceptibility (A*01) allotypes are identified through synthesising multiple genome-wide and candidate gene studies. The authors examine the mechanisms by which diverse HLA and cognate receptor allotypes can determine the course of immune responses during herpesvirus infections and pathogenesis.

Work from multiple groups has shown that genetically driven variation in HLA expression level can affect susceptibility to infectious disease or its progression. With the expansion in accessibility both to generate and to analyse large RNA sequencing datasets, it therefore becomes increasingly important to determine allotype-specific expression metrics from these potentially quantitative studies. Here, Aguiar and colleagues compare estimates of HLA expression obtained from RNA-seq data with those obtained using more established qPCR approaches (Aguiar et al. 2023). In this valuable endeavour, the authors generated and compared equivalent datasets from 96 individuals, and correlate estimates of HLA-A, -B, and -C across the two methods. They discuss the consistencies and differences across the methods, as well as the various technical or biological nuances that can contribute to any difference observed across HLA allotypes. This work should be a go-to manual for anyone attempting to quantify (or genotype) HLA expression from any high-throughput RNA sequencing data.

Inhibitory LILRB3 (ILT5, LIR3) and activating LILRA6 (ILT8) are a homologous yet polymorphic pair of myeloid cell-receptor genes located in the leukocyte receptor complex of human chromosome 19. Although the ligands are undetermined, others in this family can bind HLA class I and are likely critical in control of infectious diseases. Bashirova and colleagues perform a detailed study of LILRB3/A6 polymorphism in a panel of European blood donors, revealing substantial protein coding and potentially regulatory variants (Bashirova et al. 2022). The authors show that non-allelic homologous recombination can generate novel genomic and functional diversity of these orphan receptors. The information uncovered will prove invaluable for future studies examining the association of this genomic region with immune-mediated disease.

Although KIR are predominantly expressed by Natural Killer (NK) cells, they can also be expressed by T cells, and the importance of this role is becoming increasingly recognised. Mora-Bitria and Asquith review the literature regarding the roles of KIR-expressing T cells in chronic viral infection and their impact on human health (Mora-Bitria and Asquith 2023). The authors discuss evidence for KIR-mediated modulation of T-cell responses and the clinical significance of this modulation, focusing on HCV, HTLV-1, and HIV-1 infections, and on the role of polymorphic KIR in disease progression. They then develop a model by which KIR expression correlates with T-cell survival, and discuss potential mechanisms regarding how this occurs and the implications. In the light of recent works identifying the control of autoimmunity by KIR- expressing T cells, the review is timely and on point.

No article on current infectious diseases would be complete without mention of SARS-CoV-2 and COVID-19, and here we present three papers on this momentous subject. In the first, Hermens and Kesmir examine the T cell-driven responses to SARS-CoV-2 and their impact on the severity of COVID-19 (Hermens and Kesmir 2023). The authors discuss the development of antibody and cellular responses to acute infection and the role of activated T cells in disease severity. They also describe the role of T cells in protection from disease and offer a well-reasoned proposal for expanding the target epitopes for vaccination beyond the spike protein. In a second paper from the Kesmir group, Brand and Kesmir analyse the evolution of spike variants and their recognition by HLA class II allotypes (Brand and Kesmir 2023). The authors perform an in silico prediction analysis of spike protein T-cell epitopes to determine which DRB1 molecules may present the peptide fragments most efficiently, and conduct simulations to model spike evolution vs population-wide HLA class II diversity. In revealing that the majority of T-helper epitopes occur outside the rapidly evolving ACE-2 receptor binding domain, the authors demonstrate that the variants of concern identified to date can still be targeted by T cell-driven immunity, even when they break through the vaccine/antibody barrier.

Finally, Srivastava and Hollenbach review the impact of immunogenomic polymorphism on the response to SARS-CoV-2 infection and the course of the disease (Srivastava and Hollenbach 2022). As part of the huge world-wide effort to understand differential responses to SARS-CoV-2, the authors discuss immune-related gene variants that have been identified so far as being associated with the course of infection. These molecules include pattern recognition receptors, chemokines, and mediators of inflammation. Paying special attention of course to HLA, the authors discuss which alleles can affect COVID-19 severity. They draw comparisons with other more established viral infections and examine how specific allotypes may help or hinder recovery or prevent reinfection. Ultimately, and with a view to aiding further vaccine design, the authors also examine how HLA variation can contribute to vaccine response.

We extend our thanks to all the anonymous reviewers, whose insightful comments and constructive suggestions have made this issue possible, and to Donna Devine for keeping us all organised and on track.