Research Article: Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4+ T Cell Immunity

Date Published: May 1, 2014

Publisher: Public Library of Science

Author(s): Stephanie Ascough, Rebecca J. Ingram, Karen K. Chu, Catherine J. Reynolds, Julie A. Musson, Mehmet Doganay, Gökhan Metan, Yusuf Ozkul, Les Baillie, Shiranee Sriskandan, Stephen J. Moore, Theresa B. Gallagher, Hugh Dyson, E. Diane Williamson, John H. Robinson, Bernard Maillere, Rosemary J. Boyton, Daniel M. Altmann, Steven R. Blanke.

http://doi.org/10.1371/journal.ppat.1004085

Abstract

Bacillus anthracis produces a binary toxin composed of protective antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). Most studies have concentrated on induction of toxin-specific antibodies as the correlate of protective immunity, in contrast to which understanding of cellular immunity to these toxins and its impact on infection is limited. We characterized CD4+ T cell immunity to LF in a panel of humanized HLA-DR and DQ transgenic mice and in naturally exposed patients. As the variation in antigen presentation governed by HLA polymorphism has a major impact on protective immunity to specific epitopes, we examined relative binding affinities of LF peptides to purified HLA class II molecules, identifying those regions likely to be of broad applicability to human immune studies through their ability to bind multiple alleles. Transgenics differing only in their expression of human HLA class II alleles showed a marked hierarchy of immunity to LF. Immunogenicity in HLA transgenics was primarily restricted to epitopes from domains II and IV of LF and promiscuous, dominant epitopes, common to all HLA types, were identified in domain II. The relevance of this model was further demonstrated by the fact that a number of the immunodominant epitopes identified in mice were recognized by T cells from humans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunity was demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified.

Partial Text

Whether viewed as a threat to human health in anthrax endemic regions, as a bioweapon, or as a potentially devastating pathogen of livestock, there is pressing need to gain better insights into the immune response to Bacillus anthracis. The urgency has been underlined by recent clusters of fatal and and near-fatal anthrax infections among European intravenous drug users [1]–[4].

While considerable attention has been devoted to the profound immune subversion mediated by anthrax toxins [46], recent human studies, including this one, show that anthrax infection can be immunogenic [4]. The role of LT in the disruption of the MAPK signalling pathways, with its consequences for the apoptosis of antigen presenting cells, specifically the lysis of dendritic cells and macrophages, might be expected to subvert host immunity and promote systemic anthrax infection. However, investigation of the inverse relationship between sensitivity to LT and resistance to infection, indicates that mice which possess alleles encoding an LT-sensitive form of Nlrp1b promote a pro-inflammatory response predominantly driven by inflamasome-mediated cell lysis and release of IL-1β [47]–[50]. The associated cell infiltration and cytokine milieu seen in early inflammation may be crucial in driving antigen presentation and T cell priming. Recent studies ranging from asymptomatic seroconversion of wool-workers to our own recent work with near lethal anthrax infection in intravenous drug users, show common themes in terms of strong induction of adaptive immunity [4], [25].

 

Source:

http://doi.org/10.1371/journal.ppat.1004085

 

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