Chronic Trichuris muris infection alters hematopoiesis and causes IFN‐γ‐expressing T‐cell accumulation in the mouse bone marrow

Abstract

Proinflammatory cytokines produced during immune responses to infectious stimuli are well-characterized to have secondary effects on the function of hematopoietic progenitor cells in the BM. However, these effects on the BM are poorly characterized during chronic infection with intestinal helminth parasites. In this study, we use the Trichuris muris model of infection and show that Th1 cell-associated, but not acute Th2 cell-associated, responses to chronic T. muris infection cause a major, transient expansion of CD48 CD150 multipotent progenitor cells in the BM that is dependent on the presence of adaptive immune cells and IFN-γ signaling. Chronic T. muris infection also broadly stimulated proliferation of BM progenitor cells including CD48 CD150 hematopoietic stem cells. This shift in progenitor activity during chronic T. muris infection correlated with a functional increase in myeloid colony formation in vitro as well as neutrophilia in the BM and peripheral blood. In parallel, we observed an accumulation of CD4 , CD8 , and CD4 CD8 (double negative) T cells that expressed IFN-γ, displaying activated and central memory-type phenotypes in the bone marrow during chronic infection. Thus, these results demonstrate that Th1 cell-driven responses in the intestine during chronic helminth infection potently influence upstream hematopoietic processes in the BM via IFN-γ.

Chronic helminth infection burden differentially affects haematopoietic cell development while ageing selectively impairs adaptive responses to infection

“…4b ) and the prportion of double negative CD4−CD8− T cells in the spleen (Fig. 4c ), which is consistent with a similar observation in the bone marrow of Trichuris muris -infected mice 49 . Intriguingly, other HSPC populations were positively correlated with adult worms and microfilariae (Fig.…”

Accelerated onset of CNS prion disease in mice co-infected with a gastrointestinal helminth pathogen during the preclinical phase

“…In the current study it is plausible that serum IFN-γ produced in response to low dose T. muris similarly affected the integrity of the blood-brain barrier in the of the co-infected mice, leading to increased infiltration of CD8+ T cells into the brain. The IFN-γ+ CD8+ T cells generated in response to low dose T. muris infection can accumulate in other sites such as the bone marrow 34 . This suggests that in addition to the increased number, the higher proportion of the CD8+ T cells found in the brains of co-infected mice may also be expressing IFN-γ.…”

“…Chronic T. muris infection is known to stimulate the development of high levels of IFN-γ+ CD8+ T cells within the gut draining lymph nodes 33 , which can accumulate in other sites such as the bone marrow 34 . Low levels of CD8+ T cells have been reported to infiltrate the brains of mice and humans during CNS prion disease 35 .…”

Immunity to gastrointestinal nematode infections

“…9,211 Chronically infected mice do not display any overt symptoms of disease, but are by no means unaffected considering that persistent T. muris infections are lethal in the absence of IL-10, 212 indicating that there is ongoing inflammation beyond the spontaneous inflammation inherent to il10 -/-mice. Indeed, chronic T. muris infection results in the accumulation of interferon-g þ T cells in the bone marrow, 213 and does not appear to protect against the development of colitis. 214,215 Furthermore, depending on the strain, chronically infected mice gain less weight than their uninfected counterparts, 216 and in some cases even acquire colitis-like symptoms, thus losing weight, 217 mirroring the malnutrition and wasting of some infected humans.…”