Systemic toxoplasma infection triggers a long-term defect in the generation and function of naive T lymphocytes

Kugler, David; Flomerfelt, Francis A.; Costa, Diego L.; Laky, Karen; Kamenyeva, Olena; Mittelstadt, Paul R.; Gress, Ronald E.; Rosshart, Stephan P.; Rehermann, Barbara; Ashwell, Jonathan D.; Sher, Alan; Janković, Dragana

doi:10.1084/jem.20151636

Cited by 25 publications

(30 citation statements)

References 75 publications

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“…Moreover, a recent study has shown that systemic T. gondii infection leads to a long-term defect in the generation and function of naive T lymphocytes (Kugler et al, 2016). However, our findings suggest that in a low-dose infection with T. gondii , this effect is not as drastic,since helminth-specific CD4 + T cells were shown to proliferate and respond to antigen as seen in Figure 5.…”

Section: Discussionmentioning

confidence: 99%

Toxoplasma Co-infection Prevents Th2 Differentiation and Leads to a Helminth-Specific Th1 Response

Ahmed

French

Kühl³

et al. 2017

Front. Cell. Infect. Microbiol.

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Nematode infections, in particular gastrointestinal nematodes, are widespread and co-infections with other parasites and pathogens are frequently encountered in humans and animals. To decipher the immunological effects of a widespread protozoan infection on the anti-helminth immune response we studied a co-infection with the enteric nematode Heligmosomoides polygyrus in mice previously infected with Toxoplasma gondii. Protective immune responses against nematodes are dependent on parasite-specific Th2 responses associated with IL-4, IL-5, IL-13, IgE, and IgG1 antibodies. In contrast, Toxoplasma gondii infection elicits a strong and protective Th1 immune response characterized by IFN-γ, IL-12, and IgG2a antibodies. Co-infected animals displayed significantly higher worm fecundity although worm burden remained unchanged. In line with this, the Th2 response to H. polygyrus in co-infected animals showed a profound reduction of IL-4, IL-5, IL-13, and GATA-3 expressing T cells. Co-infection also resulted in the lack of eosinophilia and reduced expression of the Th2 effector molecule RELM-β in intestinal tissue. In contrast, the Th1 response to the protozoan parasite was not diminished and parasitemia of T. gondii was unaffected by concurrent helminth infection. Importantly, H. polygyrus specific restimulation of splenocytes revealed H. polygyrus-reactive CD4+ T cells that produce a significant amount of IFN-γ in co-infected animals. This was not observed in animals infected with the nematode alone. Increased levels of H. polygyrus-specific IgG2a antibodies in co-infected mice mirrored this finding. This study suggests that polarization rather than priming of naive CD4+ T cells is disturbed in mice previously infected with T. gondii. In conclusion, a previous T. gondii infection limits a helminth-specific Th2 immune response while promoting a shift toward a Th1-type immune response.

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Section: Discussionmentioning

confidence: 99%

Toxoplasma Co-infection Prevents Th2 Differentiation and Leads to a Helminth-Specific Th1 Response

Ahmed

French

Kühl³

et al. 2017

Front. Cell. Infect. Microbiol.

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“…Pathological changes in thymus during M avium infection‐induced tolerance to microbial antigens, thereby favouring long‐term bacterial persistence . In addition, the thymic atrophy can lead to generalized immunosuppression which affects not only pathogen‐specific, but also effector T cells clones specific to other antigens . Our findings indicate that AD activity may be a part of the pathogen survival strategy that contributes to immunosuppression at least due to thymic involution and an increased Treg generation.…”

Section: Discussionmentioning

confidence: 72%

“…Acute thymopoiesis disorder, which accompanies bacterial, viral, parasitic and fungal infections,is not limited to the reduction of thymic cellularity. Indeed, structural alterations of the thymus caused by infection modify the characteristics of differentiating T cells and affect T cell export . Pathological changes in thymus during M avium infection‐induced tolerance to microbial antigens, thereby favouring long‐term bacterial persistence .…”

Section: Discussionmentioning

confidence: 99%

Role of arginine deiminase in thymic atrophy during experimental Streptococcus pyogenes infection

et al. 2019

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Expression of gene of arginine deiminase (AD) allows adaptation of Streptococcus pyogenes to adverse environmental conditions. AD activity can lead to L‐arginine deficiency in the host cells’ microenvironment. Bioavailability of L‐arginine is an important factor regulating the functions of the immune cells in mammals. By introducing a mutation into S pyogenes M46‐16, we obtained a strain with inactivated arcA/sagp gene (M49‐16 delArcA), deficient in AD. This allowed elucidating the function of AD in pathogenesis of streptococcal infection. The virulence of the parental and mutant strains was examined in a murine model of subcutaneous streptococcal infection. L‐arginine concentration in the plasma of mice infected with S pyogenes M49‐16 delArcA remained unchanged in course of the entire experiment. At the same time mice infected with S pyogenes M49‐16 demonstrated gradual diminution of L‐arginine concentration in the blood plasma, which might be due to the activity of streptococcal AD. Mice infected with S pyogenes M49‐16 delArcA demonstrated less intensive bacterial growth in the primary foci and less pronounced bacterial dissemination as compared with animals infected with the parental strain S pyogenes M46‐16. Similarly, thymus involution, alterations in apoptosis, thymocyte subsets and Treg cells differentiation were less pronounced in mice infected with S pyogenes M49‐16 delArcA than in those infected with the parental strain. The results obtained showed that S pyogenes M49‐16 delArcA, unable to produce AD, had reduced virulence in comparison with the parental S pyogenes M49‐16 strain. AD is an important factor for the realization of the pathogenic potential of streptococci.

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“…It was recently shown that these features, including loss of NK mediated cytotoxicity and decreased spleen cellularity, may be considered as manifestations of premature immunity senescence . The link between premature immunosenescence and infection has recently been discovered for thymus and T‐lymphocytes infected by toxoplasma and cytomegalovirus …”

Section: Discussionmentioning

confidence: 99%

Natural killer cell activity irreversibly decreases after Cryptosporidium gastroenteritis in neonatal mice

Filatova

Knyazev

Skarlato

et al. 2018

Parasite Immunology

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Cryptosporidiosis causes persistent diarrhoea in infants, immunocompromised patients and elderly persons. Long-term consequences of the disease include increased risk of malignancy, cardiomyopathy and gastrointestinal inflammation. This study aimed to investigate prolonged effects of cryptosporidiosis on innate immunity and growth in neonatal C3HA mice. The disease was challenged by Cryptosporidium parvum oocyst inoculation into 7-day-old animals. The mice whose intestine smears contained 3-5 or 6 and more oocysts per microscopic field at the day 5 after infection were considered as mildly or severely infected, correspondingly. To determine natural killer cell (NK) activity, we applied H-uridine cytotoxic assay to the animals at 5-68 days after infection using K562 cells as targets. At severe infection, there was a statistically significant 1.5-2.0 fold decline of body mass, spleen mass and spleen cellularity that persisted in animals of all ages. Accordingly, NK cytotoxicity showed even more drastic drop reaching 2.7-3.0 folds that was statistically significant in all animals. At mild infection, the discovered effects were less pronounced and reached significance only in some age groups. Thus, our study provides evidence that NK cells show long-term cytotoxic activity decrease following Cryptosporidium infection in neonatal mice, particularly in severe disease.

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Systemic toxoplasma infection triggers a long-term defect in the generation and function of naive T lymphocytes

Abstract: Kugler et al. show that systemic infection with Toxoplasma gondii triggers a long-term impairment in thymic function, which leads to an immunodeficient state reflected in decreased antimicrobial resistance.

Cited by 25 publications

References 75 publications

Toxoplasma Co-infection Prevents Th2 Differentiation and Leads to a Helminth-Specific Th1 Response

Toxoplasma Co-infection Prevents Th2 Differentiation and Leads to a Helminth-Specific Th1 Response

Role of arginine deiminase in thymic atrophy during experimental Streptococcus pyogenes infection

Natural killer cell activity irreversibly decreases after Cryptosporidium gastroenteritis in neonatal mice

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