Resistance to IntestinalEntamoeba histolyticaInfection Is Conferred by Innate Immunity and Gr-1⁺Cells

Abstract

Establishment of intestinal infection with Entamoeba histolytica depends on the mouse strain; C57BL/6 mice are highly resistant, and C3H/HeJ mice are relatively susceptible. We found that resistance to intestinal infection was independent of lymphocyte activity or H-2 haplotype and occurred in the first hours to days postchallenge according to in vivo imaging. At 18 h postchallenge, the ceca of resistant C57BL/6 mice were histologically unremarkable, in contrast to the severe inflammation observed in susceptible C3H/HeJ mice. Comparison of cecal gene expression in C3H/HeJ and C57BL/6 mice demonstrated that there was parasiteinduced upregulation of proinflammatory and neutrophil chemotaxis transcripts and there was downregulation of transforming growth factor ␤ signaling molecules. Pretreatment with dexamethasone abrogated the partial resistance of C3H/HeJ or CBA mice through an innate, lymphocyte-independent mechanism, but it had no effect on the high-level resistance of C57BL/6 mice. Similarly, administration of a neutrophil-depleting anti-Gr-1 monoclonal antibody (RB6-8C5) decreased the partial resistance of CBA mice and led to severe pathology compared to control antibody-treated mice, but it had no effect on C57BL/6 resistance. These data indicate that there are discrete mechanisms of innate resistance to E. histolytica depending on the host background and, in contrast to other reports, imply that neutrophils are protective and not damaging in intestinal amebiasis.

Neutrophils and Macrophages Cooperate in Host Resistance againstLeishmania braziliensisInfection

“…Neutrophils have been shown to play an active role in the control of infections with specific and distinct pathogens such as Legionella (17), Toxoplasma (27), Mycobacterium (28), Entamoeba (29), Histoplasma (30), and Cryptosporidium (31). BALB/c mice infected in the ear dermis with L. braziliensis develop cutaneous lesions at the site of inoculation and histological analyses of infected ear sections have demonstrated a constant recruitment of neutrophils to the inoculation site (14).…”

Resistance of C57BL/6 Mice to Amoebiasis Is Mediated by Nonhemopoietic Cells but Requires Hemopoietic IL-10 Production

“…As this timing suggests, their resistance is innate and persists in B6 SCID mice (9). In contrast to susceptible mouse strains, the B6 response to amoeba histologically demonstrates a normal mucosa without inflammation or epithelial breakdown.…”

“…A majority of CBA or C3H (either TLR4 mutant or wild-type (WT)) 3 mice develop patent infections upon challenge. Early after infection, viable amoeba are seen predominantly at sites of epithelial breakdown and a robust inflammatory response ensues that is phenotypically protective, insofar as neutrophil-depleted or dexamethasone-treated C3H or CBA mice show increased infection rates and/or disease scores (9).…”

“…In contrast to susceptible mouse strains, the B6 response to amoeba histologically demonstrates a normal mucosa without inflammation or epithelial breakdown. Indeed, gene expression analysis suggests the absence of a response to amoeba in B6 mice (only 1 of 12,422 genes or expressed sequence tag was dysregulated between B6 sham-and B6 amoeba-challenged mice; data published in (9) and available at ͗https://genes.med.virginia.edu/public data/index.cgi͘). Moreover, B6 resistance does not rely on an innate proinflammatory response in that IL-12p40-deficient, inducible NO synthase-deficient, phagocyte oxidase-deficient, MyD88-deficient, or neutrophil-depleted B6 mice remain resistant (8,9).…”

“…To define the host mechanisms of resistance to intestinal amoebiasis, we have used a mouse model of amoebic colitis that develops upon intracecal inoculation of trophozoites (4,8,9). A majority of CBA or C3H (either TLR4 mutant or wild-type (WT)) 3 mice develop patent infections upon challenge.…”