Role of genetic heterogeneity in determining the epidemiological severity of H1N1 influenza

Genetic differences contribute to variations in the immune response mounted by different individuals to a pathogen. Such differential response can influence the spread of infectious disease, indicating why such diseases impact some populations more than others. Here, we study the impact of population-level genetic heterogeneity on the epidemic spread of different strains of H1N1 influenza. For a population with known HLA class-I allele frequency and for a given H1N1 viral strain, we classify individuals into sub-populations according to their level of susceptibility to infection. Our core hypothesis is that the susceptibility of a given individual to a disease such as H1N1 influenza is inversely proportional to the number of high affinity viral epitopes the individual can present. This number can be extracted from the HLA genetic profile of the individual. We use ethnicity-specific HLA class-I allele frequency data, together with genome sequences of various H1N1 viral strains, to obtain susceptibility sub-populations for 61 ethnicities and 81 viral strains isolated in 2009, as well as 85 strains isolated in other years. We incorporate these data into a multi-compartment SIR model to analyse the epidemic dynamics for these (ethnicity, viral strain) epidemic pairs. Our results show that HLA allele profiles which lead to a large spread in individual susceptibility values can act as a protective barrier against the spread of influenza. We predict that populations skewed such that a small number of highly susceptible individuals coexist with a large number of less susceptible ones, should exhibit smaller outbreaks than populations with the same average susceptibility but distributed more uniformly across individuals. Our model tracks some well-known qualitative trends of influenza spread worldwide, suggesting that HLA genetic diversity plays a crucial role in determining the spreading potential of different influenza viral strains across populations.

遗传差异会导致不同个体对病原体产生的免疫应答存在差异。这类差异化的免疫应答可影响传染病的传播，这也解释了为何此类疾病对部分人群的影响更为严重。本研究针对人群水平的遗传异质性对不同甲型H1N1流感毒株流行传播的影响展开探究。针对已知人类白细胞抗原（HLA）I类等位基因频率的人群，以及特定甲型H1N1流感毒株，我们依据个体的感染易感性水平将其划分为不同亚群。我们的核心假说为：个体对甲型H1N1流感等疾病的易感性，与其能够呈递的高亲和力病毒表位数量呈负相关；该数量可通过个体的HLA遗传图谱获取。我们利用种族特异性HLA I类等位基因频率数据，结合不同甲型H1N1流感毒株的基因组序列，分别针对61个种族、81株2009年分离的毒株以及85株其他年份分离的毒株，得到了对应的易感性亚群。我们将上述数据整合至多室易感-感染-移除（SIR）模型中，以分析每一组（种族、毒株）对应的流行病传播动力学。研究结果表明，个体易感性数值分布跨度较大的HLA等位基因图谱，可成为抵御流感传播的保护屏障。我们预测，若某人群呈现出“少数个体易感性极强，多数个体易感性较弱”的偏态分布，相较于易感性均值相同但个体间易感性分布更均匀的人群，前者的疫情暴发规模会更小。本模型能够复现全球范围内流感传播的部分已知定性趋势，这表明HLA遗传多样性在决定不同流感毒株在人群中的传播潜力方面发挥着关键作用。