Streptococcal Immunity Is Constrained by Lack of Immunological Memory following a Single Episode of Pyoderma

Abstract

The immunobiology underlying the slow acquisition of skin immunity to group A streptococci (GAS), is not understood, but attributed to specific virulence factors impeding innate immunity and significant antigenic diversity of the type-specific M-protein, hindering acquired immunity. We used a number of epidemiologically distinct GAS strains to model the development of acquired immunity. We show that infection leads to antibody responses to the serotype-specific determinants on the M-protein and profound protective immunity; however, memory B cells do not develop and immunity is rapidly lost. Furthermore, antibodies do not develop to a conserved M-protein epitope that is able to induce immunity following vaccination. However, if re-infected with the same strain within three weeks, enduring immunity and memory B-cells (MBCs) to type-specific epitopes do develop. Such MBCs can adoptively transfer protection to naïve recipients. Thus, highly protective M-protein-specific MBCs may never develop following a single episode of pyoderma, contributing to the slow acquisition of immunity and to streptococcal endemicity in at-risk populations.

Epidemiological consequences of enduring strain-specific immunity requiring repeated episodes of infection

“…In the mouse model [31], the effect of the immune response was assessed by determining the number of colony forming units in skin and blood samples (bioburden) collected six days post inoculation. These showed a reduction in bioburden of approximately 90% for second infections of the same serotype compared to the first infection, provided that the second infection occurred within three weeks of the first.…”

“…Values for parameters relating to the effects of immunity are determined from the 229 mouse model of GAS skin infection [31]. We set the strength of temporary strain-specific 230 immunity σ to 0.9 and the strength of temporary and enduring cross-strain immunity to 231 0.1.…”

“…We set the strength of temporary strain-specific 230 immunity σ to 0.9 and the strength of temporary and enduring cross-strain immunity to 231 0.1. These values are based on the respective observations of 90% and 0-30% reduction 232 in bioburden in the mouse due to strain-specific and cross-strain immunity [31].…”

“…The maximum inter-infection interval w was estimated to be three weeks in the mouse 239 model [31]. It is not clear how this timespan translates in humans.…”

“…Current consensus is that the 399 immune response to GAS infection is largely strain (serotype)-specific [25]. Recent 400 evidence in a murine model of GAS skin infection raises the possibility that the longevity 401 of this immune response may be contingent on individuals experiencing a repeat episode 402 of infection by the same strain within a narrow time window [31]. As yet, there is no transmissibility has competing effects on the likelihood of hosts acquiring enduring immunity in our model, which leads to a complex relationship between transmissibility 440 and prevalence.…”