Antigen-Specific CD4+CD8+ Double-Positive T Cells Are Increased in the Blood and Spleen During Ehrlichia chaffeensis Infection in the Canine Host

Abstract

Ehrlichia chaffeensis is an obligate intracellular bacterium belonging to the order, Rickettsiales and is a frequent cause of severe and fatal tick-borne infection in people in North America. The reservoir host for E. chaffeensis is the white-tailed deer, while humans and dogs are regarded as common incidental hosts. In dogs, we and others have shown that E. chaffeensis establishes a chronic infection that persists for several weeks to months, while promoting the development of Th1 and Th17 cellular responses and pathogen-specific humoral immunity. We demonstrate here that vaccination with a live, attenuated clone of E. chaffeensis bearing a targeted mutation in the Ech_0230 gene neither promotes the development of long-lived cellular or humoral immunity, nor confers protection against secondary wild-type E. chaffeensis challenge. In dogs, a population of mature CD4+CD8+ double-positive (DP) T cells exists in the periphery that shares similarities with the DP T cell populations that have been described in humans and swine. Little is known about the function of these cells, particularly in the context of infectious diseases. Here, we demonstrate that canine DP T cells expand significantly in response to E. chaffeensis infection. Using in vitro antigen recall assays, we further demonstrate that canine DP T cells undergo clonal expansion, produce IFNγ and IL-17, and upregulate expression of granzyme B and granulysin. Together, our results demonstrate that DP T cells accumulate in the host during E. chaffeensis infection, and suggest that alternative lymphocyte populations may participate in the immune response to tick-borne infections in the incidental host.

Multiple Ehrlichia chaffeensis Genes Critical for Its Persistent Infection in a Vertebrate Host Are Identified by Random Mutagenesis Coupled with In Vivo Infection Assessment

“…These studies aided in the identification of one mutation in ECH_0660 gene causing the rapid clearance of the pathogen and inducing a sufficient host immune response to serve as a live attenuated vaccine to protect against wild type infection challenge by intravenous (IV) infection, as well as by tick transmission (16,17). Mutagenized E. chaffeensis organisms are also valuable in studies focused on understanding the host response against the pathogen (17,18).…”

“…We further reported that Himar1 transposase-based random mutagenesis is efficient in creating mutations in both protein-coding and noncoding regions of the pathogen ( 14 ). We demonstrated that Himar1 mutagenesis is a valuable tool in elucidating host-pathogen interactions and in developing attenuated mutant vaccines ( 16 – 18 ). Similarly, random mutagenesis is described for other members of the alphaproteobacterial order Rickettsiales ( 19 – 24 ).…”

Food allergen-specific sublingual immunotherapy modulates peripheral T cell responses of dogs with adverse food reactions

“…In swine, DP T cells are a multifunctional memory T cell subset involved in protection against viral infections (Gerner et al, 2015;Okutani et al, 2018), while in humans this T cell subset is associated with chronic diseases, including atopic dermatitis (Bang et al, 2001;Overgaard et al, 2015). Only a few reports describe these CD4+CD8+ DP T cells in dogs and they seem to have an activated phenotype (Bismarck et al, 2012(Bismarck et al, , 2014Hoshino et al, 2008;Kato et al, 2007;McGill et al, 2018), but their function remains largely unclear. Recently, canine CD4+CD8+ DP T cells were shown to expand upon infection with Ehrlichia chaffeensis, an obligate intracellular bacterium causing chronic infections in dogs (McGill et al, 2018).…”

“…Only a few reports describe these CD4+CD8+ DP T cells in dogs and they seem to have an activated phenotype (Bismarck et al, 2012(Bismarck et al, , 2014Hoshino et al, 2008;Kato et al, 2007;McGill et al, 2018), but their function remains largely unclear. Recently, canine CD4+CD8+ DP T cells were shown to expand upon infection with Ehrlichia chaffeensis, an obligate intracellular bacterium causing chronic infections in dogs (McGill et al, 2018). In our study, dogs with AFR had a higher baseline value of DP T cells than that reported in healthy dogs (25% vs 2.4%, resp.)…”

Immunophenotyping of Peripheral Blood, Lymph Node, and Bone Marrow T Lymphocytes During Canine Leishmaniosis and the Impact of Antileishmanial Chemotherapy

“…CD4 + CD8 + dp T cells have been identified in dogs with and without CanL ( 56 , 90 , 91 ). In the current study, the frequency of CD4 + CD8 + dp T cell subsets was revealed to be increased in peripheral blood, lymph node, and bone marrow of dogs with CanL.…”