Consequences of host heterogeneity, epitope immunodominance, and immune breadth for strain competition

Abstract

Consumer-resource dynamics of hosts with their pathogens are modulated by complex interactions between various branches of hosts' immune systems and the imperfectly perceived pathogen. Multistrain SIR models tend to sweep competitive interaction terms between different pathogen strains into a single parameter representing cross-immunity. After reviewing several hypotheses about the generation of immune responses, we look into the consequences of assuming that hosts with identical immune repertoires respond to new pathogens identically. In particular, we vary the breadth of the typical immune response, or the average number of pathogen epitopes a host perceives, and the probability of perceiving a particular epitope. The latter quantity in our model is equivalent both to the degree of diversity in host responses at the population level and the relative immunodominance of different epitopes. We find that a sharp transition to strain coexistence occurs as host responses become narrow or skewed toward one epitope. Increasing the breadth of the immune response and the immunogenicity of different epitopes typically increases the range of cross-immunity values in which chaotic strain dynamics and competitive exclusion occur. Models attempting to predict the outcomes of strain competition should thus consider the potential diversity and specificity of hosts' responses to infection.

Figure 1

Three possible mechanisms of heterogeneity in hosts’ immune responses. Hosts are immunologically naïve before the first challenge. Each of the three circles in a strain corresponds to a different epitope/locus; each color corresponds to a different phenotype/allele at that epitope/locus. Circles crossed in red represent specific adaptive immune responses (e.g., antibodies or T-cells) to a particular phenotype/allele. The presence of horizontal lines preceding them indicates activation of one or more preexisting responses, which confer protection. (a) Original antigenic sin (OAS). OAS posits that strains that are closely antigenically related may not inspire novel immune responses. Thus, hosts exposed to the same strains but in different sequences will accumulate different immune repertoires and can respond differently upon infection with the same challenge strain. This example shows OAS with a multilocus and polyclonal response; it can also operate for a single locus and monoclonal response. (b) Random immunodominance. This mechanism, the basis of the model explored in this paper, assumes that hosts usually only perceive or develop a strong response to a subset (here, one) of available epitopes. Epitopes have certain probabilities of being immunodominant, and these probabilities do not vary among hosts. (c) Predetermined immunodominance. Hosts intrinsically vary in their propensities to mount immune responses to different epitopes. Host A recognizes only the first locus, and host B only the third. Host A thus perceives three distinct strains and host B two distinct strains.

Figure 2

Equilibrium strain dynamics generated with monoclonal (c = 1) and polyclonal (c > 1) host responses for different levels of host diversity or epitope immunodominance b for the three locus (n = 3), two allele (m = 2) case. The color of each point indicates the number of strains with an infection prevalence below 10⁻⁸ at that time.

Figure 3

Sample time series showing transients of z_i, w_i, and y_i with γ = 0.75, c = 1, and b = 0.85. Each color corresponds to a different strain. Note differences in the ranges of the y-axes between plots.

Figure 4

Sample time series showing transients of z_i, w_i, and y_i with γ = 0.95, c = 2, and b = 0. Each color corresponds to a different strain.