Nonencapsulated Trichinella pseudospiralis Infection Impairs Follicular Helper T Cell Differentiation with Subclass-Selective Decreases in Antibody Responses

Infectious microorganisms often modify host immunity to escape from immune elimination. Trichinella is a unique nematode of the helminth family, whose members parasitize the muscle cells inside the host without robust eliminative reactions. There are several species of Trichinella ; some develop in muscle cells that become encapsulated (e.g., Trichinella spiralis ) and others in cells that do not encapsulate (e.g., Trichinella pseudospiralis ). It has already been established that Trichinella infection affects host immune responses in several experimental immune diseases in animal models; however, most of those studies were done using T. spiralis infection. As host immune responses to T. spiralis and T. pseudospiralis infections have been reported to be different, it is necessary to clarify how T. pseudospiralis infection influences the host immune responses. In this study, we investigated the influence on host humoral immunity in T. pseudospiralis -infected mice. We demonstrated that T. pseudospiralis infection decreased antigen-specific IgG2a and IgG2b antibody (Ab) production in mice immunized with a model antigen. This selective decrease in gamma interferon (IFN-γ)-dependent Ab production was not due to a decrease in IFN-γ production, and we instead found impaired follicular helper T (Tfh) cell differentiation. The affinity maturation of antigen-specific Ab tended to be delayed but was not significant in T. pseudospiralis -infected mice. We also observed that CD11b + spleen cells in T. pseudospiralis -infected mice expressed CD206 and PD-L2, the phenotype of which was M2 macrophages with weak production of interleukin-6 (IL-6), possibly resulting in impaired Tfh differentiation. Taken together, our results indicate that nonencapsulated Trichinella infection induces selective dampening in humoral immunity with the suppression of Tfh differentiation.

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Genetic Screen inChlamydia muridarumReveals Role for an Interferon-Induced Host Cell Death Program in Antimicrobial Inclusion Rupture

mBio ◽

10.1128/mbio.00385-19 ◽

2019 ◽

Vol 10 (2) ◽

Cited By ~ 4

Author(s):

Amanda M. Giebel ◽

Shuai Hu ◽

Krithika Rajaram ◽

Ryan Finethy ◽

Evelyn Toh ◽

...

Keyword(s):

Cell Death ◽

Immune Responses ◽

Host Cell ◽

Host Defense ◽

Genetic Screen ◽

Content Type ◽

Host Immune Responses ◽

Interferon Stimulated Genes ◽

Host Cell Death ◽

Ifn Γ

ABSTRACTInterferon-regulated immune defenses protect mammals from pathogenically diverse obligate intracellular bacterial pathogens of the genusChlamydia. Interferon gamma (IFN-γ) is especially important in controlling the virulence ofChlamydiaspecies and thus impacts the modeling of human chlamydial infection and disease in mice. How IFN-γ contributes to cell-autonomous defenses againstChlamydiaspecies and how these pathogens evade IFN-γ-mediated immunity in their natural hosts are not well understood. We conducted a genetic screen which identified 31IFN-γ-sensitive (Igs) mutants of the mouse model pathogenChlamydia muridarum. Genetic suppressor analysis and lateral gene transfer were used to map the phenotype of one of these mutants, Igs4, to a missense mutation in a putative chlamydial inclusion membrane protein, TC0574. We observed the lytic destruction of Igs4-occupied inclusions and accompanying host cell death in response to IFN-γ priming or various proapoptotic stimuli. However, Igs4 was insensitive to IFN-γ-regulated cell-autonomous defenses previously implicated in anti-Chlamydia trachomatishost defense in mice. Igs4 inclusion integrity was restored by caspase inhibitors, indicating that the IFN-γ-mediated destruction of Igs4 inclusions is dependent upon the function of caspases or related prodeath cysteine proteases. We further demonstrated that the Igs4 mutant is immune restricted in an IFN-γ-dependent manner in a mouse infection model, thereby implicating IFN-γ-mediated inclusion destruction and host cell death as potentin vivohost defense mechanisms to which wild-typeC. muridarumis resistant. Overall, our results suggest thatC. muridarumevolved resistance mechanisms to counter IFN-γ-elicited programmed cell death and the associated destruction of intravacuolar pathogens.IMPORTANCEMultiple obligatory intracellular bacteria in the genusChlamydiaare important pathogens. In humans, strains ofC. trachomatiscause trachoma, chlamydia, and lymphogranuloma venereum. These diseases are all associated with extended courses of infection and reinfection that likely reflect the ability of chlamydiae to evade various aspects of host immune responses. Interferon-stimulated genes, driven in part by the cytokine interferon gamma, restrict the host range of variousChlamydiaspecies, but how these pathogens evade interferon-stimulated genes in their definitive host is poorly understood. VariousChlamydiaspecies can inhibit death of their host cells and may have evolved this strategy to evade prodeath signals elicited by host immune responses. We present evidence that chlamydia-induced programmed cell death resistance evolved to counter interferon- and immune-mediated killing ofChlamydia-infected cells.

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Immunostimulatory Effects of Recombinant Erysipelothrix rhusiopathiae Expressing Porcine Interleukin-18 in Mice and Pigs

Clinical and Vaccine Immunology ◽

10.1128/cvi.00342-12 ◽

2012 ◽

Vol 19 (9) ◽

pp. 1393-1398 ◽

Cited By ~ 2

Author(s):

Yohsuke Ogawa ◽

Yu Minagawa ◽

Fang Shi ◽

Masahiro Eguchi ◽

Yoshihiro Muneta ◽

...

Keyword(s):

Immune Responses ◽

Peritoneal Macrophages ◽

Erysipelothrix Rhusiopathiae ◽

Interleukin 18 ◽

Murine Splenocytes ◽

Content Type ◽

Immunostimulatory Effect ◽

Ifn Γ ◽

Acquired Immune Responses

ABSTRACTInterleukin-18 (IL-18), which was originally called gamma interferon (IFN-γ)-inducing factor, has been shown to play an important role in innate and acquired immune responses. In this study, attenuatedErysipelothrix rhusiopathiaestrains were engineered to produce porcine IL-18 (poIL-18) and evaluated for their potential immunostimulatory effect in animals. Recombinant poIL-18 was successfully expressed in the recombinantE. rhusiopathiaestrains YS-1/IL-18 and KO/IL-18. The culture supernatant of YS-1/IL-18 was confirmed to induce IFN-γ production in murine splenocytesin vitro, and this production was inhibited by incubation with anti-poIL-18 monoclonal antibodies. Furthermore, more IFN-γ production was induced upon stimulation of splenocytes with concanavalin A for splenocytes from mice that were intraperitoneally inoculated with YS-1/IL-18 than for splenocytes from control mice inoculated with the parent strain YS-1. Peritoneal macrophages from mice preinoculated with YS-1/IL-18 exhibited enhanced phagocytosis ofSalmonella entericasubsp.entericaserovar Typhimurium compared with peritoneal macrophages from control mice preinoculated with YS-1. We also confirmed the immunostimulatory effect on humoral immune responses against antigens ofE. rhusiopathiaeandMycoplasma hyopneumoniaein gnotobiotic pigs that were orally preinoculated with KO/IL-18. Thus, these results provide evidence thatE. rhusiopathiaeis a promising vector for the expression of host cytokines and suggest the potential utility ofE. rhusiopathiaevector-encoded cytokines in the activation of host innate and acquired immune responses.

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P105 Glutathione S-transferase theta 1 protects against colitis through goblet cell differentiation via interleukin-22

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.234 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S188-S188

Author(s):

J H Kim ◽

J B Ahn ◽

D H Kim ◽

S Kim ◽

H W Ma ◽

...

Keyword(s):

Cell Differentiation ◽

Immune Responses ◽

Goblet Cell ◽

Goblet Cells ◽

Dependent Manner ◽

Glutathione S Transferase ◽

Host Immune Responses ◽

Interleukin 22 ◽

Gstt1 Gene ◽

Goblet Cell Differentiation

Abstract Background The enzyme glutathione S-transferase theta 1 (GSTT1) is involved in detoxifying chemicals, including reactive oxygen species (ROS). Oxidative stress plays a key role in the pathogenesis of inflammatory bowel disease (IBD). Although mutation of the GSTT1 gene increases IBD susceptibility, the underlying mechanisms remain unexplained. Methods The Gstt1 gene was intrarectally or intraperitoneally delivered to mice with dextran sodium sulphate (DSS)-induced colitis. The GSTT1 gene was knocked down or knocked out using short interfering RNA or genome editing, respectively. Protein and mRNA expression and differentiation of goblet cells were evaluated. Results We identified decreased expression of GSTT1 in inflamed tissues from IBD patients and mice compared with their control counterparts, respectively. We also noted attenuation of colitis through gene transfer of Gstt1 to DSS-treated mice via the interleukin-22 (IL-22) pathway. GSTT1 was differently regulated by pathogens and host immune responses. Down-regulation of GSTT1 reduced innate defence responses and goblet cell differentiation. The GSTT1 mutation in intestinal epithelial cells as well as IBD patients diminished its dimerisation, which was connected to insufficient phosphorylation of signal transducer and activator of transcription 3 and p38/mitogen-activated protein kinase by their common activator, IL-22. Conclusion GSTT1 ameliorated IL-22 in colitis in a dependent manner and contributed as a modulator of goblet cells through sensing pathogens and host immune responses. Its mutations are linked to chronic intestinal inflammation due to its insufficient dimerisation. Our results provide new insights into GSTT1 mutations and their functional consequences in IBDs.

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Host Immune Response and Novel Diagnostic Approach to NTM Infections

International Journal of Molecular Sciences ◽

10.3390/ijms21124351 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4351

Author(s):

Yuko Abe ◽

Kiyoharu Fukushima ◽

Yuki Hosono ◽

Yuki Matsumoto ◽

Daisuke Motooka ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Humoral Immunity ◽

Diagnostic Approach ◽

Post Transplantation ◽

Diagnosis And Management ◽

Immunological Responses ◽

Host Immune Responses ◽

Diagnostic Approaches ◽

Proper Diagnosis

The incidence and prevalence of non-tuberculous mycobacteria (NTM) infections are steadily increasing worldwide, partially due to the increased incidence of immunocompromised conditions, such as the post-transplantation state. The importance of proper diagnosis and management of NTM infection has been recently recognized. Host immunological responses play integral roles in vulnerability to NTM infections, and may contribute to the onset of specific types of NTM infection. Furthermore, distinct NTM species are known to affect and attenuate these host immune responses in unique manners. Therefore, host immune responses must be understood with respect to each causative NTM species. Here, we review innate, cellular-mediated, and humoral immunity to NTM and provide perspectives on novel diagnostic approaches regarding each NTM species.

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Immediate Interferon Gamma Induction Determines Murine Host Compatibility Differences between Toxoplasma gondii and Neospora caninum

Infection and Immunity ◽

10.1128/iai.00027-20 ◽

2020 ◽

Vol 88 (4) ◽

Cited By ~ 1

Author(s):

Rachel S. Coombs ◽

Matthew L. Blank ◽

Elizabeth D. English ◽

Yaw Adomako-Ankomah ◽

Ifeanyi-Chukwu Samuel Urama ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Immune Responses ◽

Interferon Gamma ◽

Neospora Caninum ◽

Ectopic Expression ◽

Parasite Burden ◽

Interleukin 12 ◽

Content Type ◽

Ifn Γ ◽

And Control

ABSTRACT Rodents are critical for the transmission of Toxoplasma gondii to the definitive feline host via predation, and this relationship has been extensively studied as a model for immune responses to parasites. Neospora caninum is a closely related coccidian parasite of ruminants and canines but is not naturally transmitted by rodents. We compared mouse innate immune responses to N. caninum and T. gondii and found marked differences in cytokine levels and parasite growth kinetics during the first 24 h postinfection (hpi). N. caninum-infected mice produced significantly higher levels of interleukin-12 (IL-12) and interferon gamma (IFN-γ) by as early as 4 hpi, but the level of IFN-γ was significantly lower or undetectable in T. gondii-infected mice during the first 24 hpi. “Immediate” IFN-γ and IL-12p40 production was not detected in MyD88−/− mice. However, unlike IL-12p40−/− and IFN-γ−/− mice, MyD88−/− mice survived N. caninum infections at the dose used in this study. Serial measures of parasite burden showed that MyD88−/− mice were more susceptible to N. caninum infections than wild-type (WT) mice, and control of parasite burdens correlated with a pulse of serum IFN-γ at 3 to 4 days postinfection in the absence of detectable IL-12. Immediate IFN-γ was partially dependent on the T. gondii mouse profilin receptor Toll-like receptor 11 (TLR11), but the ectopic expression of N. caninum profilin in T. gondii had no impact on early IFN-γ production or parasite proliferation. Our data indicate that T. gondii is capable of evading host detection during the first hours after infection, while N. caninum is not, and this is likely due to the early MyD88-dependent recognition of ligands other than profilin.

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Mycobacterium tuberculosisLipoprotein and Lipoglycan Binding to Toll-Like Receptor 2 Correlates with Agonist Activity and Functional Outcomes

Infection and Immunity ◽

10.1128/iai.00450-18 ◽

2018 ◽

Vol 86 (10) ◽

Cited By ~ 10

Author(s):

Supriya Shukla ◽

Edward T. Richardson ◽

Michael G. Drage ◽

W. Henry Boom ◽

Clifford V. Harding

Keyword(s):

Immune Responses ◽

Agonist Activity ◽

Toll Like Receptor ◽

Necrosis Factor Alpha ◽

Tlr2 Agonist ◽

Content Type ◽

Host Immune Responses ◽

Extracellular Signal ◽

Toll Like Receptor 2 ◽

Tlr2 Signaling

ABSTRACTMycobacterium tuberculosiscauses persistent infection due to its ability to evade host immune responses.M. tuberculosisinduces Toll-like receptor 2 (TLR2) signaling, which influences immune responses toM. tuberculosis. TLR2 agonists expressed byM. tuberculosisinclude lipoproteins (e.g., LprG), the glycolipid phosphatidylinositol mannoside 6 (PIM6), and the lipoglycan lipomannan (LM). AnotherM. tuberculosislipoglycan, mannose-capped lipoarabinomannan (ManLAM), lacks TLR2 agonist activity. In contrast, PILAM, fromMycobacterum smegmatis, does have TLR2 agonist activity. Our understanding of howM. tuberculosislipoproteins and lipoglycans interact with TLR2 is limited, and binding of these molecules to TLR2 has not been measured directly. Here, we directly measuredM. tuberculosislipoprotein and lipoglycan binding to TLR2 and its partner receptor, TLR1. LprG, LAM, and LM were all found to bind to TLR2 in the absence of TLR1, but not to TLR1 in the absence of TLR2. Trimolecular interactions were revealed by binding of TLR2-LprG or TLR2-PIM6 complexes to TLR1, whereas binding of TLR2 to TLR1 was not detected in the absence of the lipoprotein or glycolipid. ManLAM exhibited low affinity for TLR2 in comparison to PILAM, LM, and LprG, which correlated with reduced ability of ManLAM to induce TLR2-mediated extracellular-signal-regulated kinase (ERK) activation and tumor necrosis factor alpha (TNF-α) secretion in macrophages. We provide the first direct affinity measurement and kinetic analysis ofM. tuberculosislipoprotein and lipoglycan binding to TLR2. Our results demonstrate that binding affinity correlates with the functional ability of agonists to induce TLR2 signaling.

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Th1/Th2 Cytokine Profile in Patients Coinfected with HIV and Leishmania in Brazil

Clinical and Vaccine Immunology ◽

10.1128/cvi.00076-11 ◽

2011 ◽

Vol 18 (10) ◽

pp. 1765-1769 ◽

Cited By ~ 7

Author(s):

Maria Zilma Andrade Rodrigues ◽

Maria Fernanda Rios Grassi ◽

Sanjay Mehta ◽

Xing-Quan Zhang ◽

Luana Leandro Gois ◽

...

Keyword(s):

Immune Responses ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Peripheral Blood Mononuclear ◽

Content Type ◽

Th2 Cytokine ◽

Cytokine Levels ◽

Blood Mononuclear Cells ◽

Ifn Γ

ABSTRACTTo evaluate the effects of HIV on immune responses in cutaneous leishmaniasis (CL), we quantified cytokine levels from plasma and stimulated peripheral blood mononuclear cells (PBMCs) from individuals infected with HIV and/or CL. Gamma interferon (IFN-γ) and interleukin 13 (IL-13) levels and the ratio of IFN-γ to IL-10 produced in response to stimulation with solubleLeishmaniaantigens were significantly lower in HIV-Leishmania-coinfected patients than in CL-monoinfected patients.

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Immune Responses of Iranian Patients with Visceral Leishmaniasis and Recovered Individuals to LCR1 of Leishmania infantum

Clinical and Vaccine Immunology ◽

10.1128/cvi.00711-13 ◽

2014 ◽

Vol 21 (4) ◽

pp. 518-525 ◽

Cited By ~ 1

Author(s):

Hamid M. Niknam ◽

Firoozeh Abrishami ◽

Mohammad Doroudian ◽

Mosayeb Rostamian ◽

Maryam Moradi ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Immune Responses ◽

Leishmania Infantum ◽

Mononuclear Cells ◽

Antibody Responses ◽

Antibody Detection ◽

Recent History ◽

Content Type ◽

History Of ◽

Ifn Γ

ABSTRACTVisceral leishmaniasis is a serious public health problem.Leishmania infantumis one of its causative agents. LCR1 is an immunogen fromL. infantum. Antibodies against this protein have been detected in visceral leishmaniasis patients. The aim of this study was to define the antibody and cellular immune responses against LCR1 in Iranian visceral leishmaniasis patients and recovered individuals. The LCR1 protein was produced in recombinant form. Antibody responses against this protein were studied in Iranian individuals with a recent history of visceral leishmaniasis. Responses of peripheral blood mononuclear cells to this protein were studied in Iranian individuals who had recovered from visceral leishmaniasis. Our data show that (i) there was an antibody response to LCR1 in each individual with a recent history of visceral leishmaniasis studied, (ii) there was neither a proliferative response nor production of gamma interferon (IFN-γ) or interleukin 10 in response to LCR1 by mononuclear cells from individuals who had recovered from visceral leishmaniasis, and (iii) individuals who have recovered from visceral leishmaniasis show ongoing immune responses long after recovery from the disease. These data show that there are no detectable cellular memory responses to LCR1 in Iranian individuals who have recovered from visceral leishmaniasis, while there are detectable antibody responses in patients with this disease. Our data suggest that LCR1 has potential applications for the diagnosis of leishmaniasis through antibody detection, while the application of LCR1 alone for induction of IFN-γ in individuals who recovered from this disease is not supported. The presence of long-lasting immune reactivities in individuals who recovered from the disease may show the necessity of extended medical surveillance for these individuals.

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Vaccination with Lentiviral Vector Expressing thenfa1Gene Confers a Protective Immune Response to Mice Infected with Naegleria fowleri

Clinical and Vaccine Immunology ◽

10.1128/cvi.00210-13 ◽

2013 ◽

Vol 20 (7) ◽

pp. 1055-1060 ◽

Cited By ~ 9

Author(s):

Jong-Hyun Kim ◽

Hae-Jin Sohn ◽

Jinyoung Lee ◽

Hee-Jong Yang ◽

Yong-Joon Chwae ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Viral Vector ◽

Lentiviral Vector ◽

Survival Rates ◽

Dna Vaccination ◽

Naegleria Fowleri ◽

Content Type ◽

Ifn Γ ◽

Nægleria Fowleri

ABSTRACTNaegleria fowleri, a pathogenic free-living amoeba, causes fatal primary amoebic meningoencephalitis (PAM) in humans and animals. Thenfa1gene (360 bp), cloned from a cDNA library ofN. fowleri, produces a 13.1-kDa recombinant protein which is located on pseudopodia, particularly the food cup structure. Thenfa1gene plays an important role in the pathogenesis ofN. fowleriinfection. To examine the effect ofnfa1DNA vaccination againstN. fowleriinfection, we constructed a lentiviral vector (pCDH) expressing thenfa1gene. For thein vivomouse study, BALB/c mice were intranasally vaccinated with viral particles of a viral vector expressing thenfa1gene. To evaluate the effect of vaccination and immune responses of mice, we analyzed the IgG levels (IgG, IgG1, and IgG2a), cytokine induction (interleukin-4 [IL-4] and gamma interferon [IFN-γ]), and survival rates of mice that developed PAM. The levels of both IgG and IgG subclasses (IgG1 and IgG2a) in vaccinated mice were significantly increased. The cytokine analysis showed that vaccinated mice exhibited greater IL-4 and IFN-γ production than the other control groups, suggesting a Th1/Th2 mixed-type immune response. In vaccinated mice, high levels of Nfa1-specific IgG antibodies continued until 12 weeks postvaccination. The mice vaccinated with viral vector expressing thenfa1gene also exhibited significantly higher survival rates (90%) after challenge withN. fowleritrophozoites. Finally, thenfa1vaccination effectively induced protective immunity by humoral and cellular immune responses inN. fowleri-infected mice. These results suggest that DNA vaccination using a viral vector may be a potential tool againstN. fowleriinfection.

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Immunization with Ehrlichia P28 Outer Membrane Proteins Confers Protection in a Mouse Model of Ehrlichiosis

Clinical and Vaccine Immunology ◽

10.1128/cvi.05292-11 ◽

2011 ◽

Vol 18 (12) ◽

pp. 2018-2025 ◽

Cited By ~ 18

Author(s):

Patricia A. Crocquet-Valdes ◽

Nagaraja R. Thirumalapura ◽

Nahed Ismail ◽

Xuejie Yu ◽

Tais B. Saito ◽

...

Keyword(s):

T Cells ◽

Membrane Proteins ◽

Immune Responses ◽

Outer Membrane ◽

Outer Membrane Proteins ◽

The United States ◽

Mononuclear Phagocytes ◽

Specific Cell ◽

Content Type ◽

Ifn Γ

ABSTRACTThe obligately intracellular bacteriumEhrlichia chaffeensisthat resides in mononuclear phagocytes is the etiologic agent of human monocytotropic ehrlichiosis (HME). HME is an emerging and often life-threatening, tick-transmitted infectious disease in the United States. Effective primary immune responses againstEhrlichiainfection involve generation ofEhrlichia-specific gamma interferon (IFN-γ)-producing CD4+T cells and cytotoxic CD8+T cells, activation of macrophages by IFN-γ, and production ofEhrlichia-specific antibodies of the Th1 isotype. Currently, there are no vaccines available against HME. We evaluated the ability of 28-kDa outer membrane proteins (P28-OMP-1) of the closely relatedEhrlichia muristo stimulate long-term protective memory T and B cell responses and confer protection in mice. The spleens of mice vaccinated withE. murisP28-9, P28-12, P28-19, or a mixture of these three P28 proteins (P28s) using a DNA prime-protein boost regimen and challenged withE. murishad significantly lower bacterial loads than the spleens of mock-vaccinated mice. Mice immunized with P28-9, P28-12, P28-19, or the mixture inducedEhrlichia-specific CD4+Th1 cells. Interestingly, mice immunized with P28-14, orthologs of which inE. chaffeensisandE. canisare primarily expressed in tick cells, failed to lower the ehrlichial burden in the spleen. Immunization with the recombinant P28-19 protein alone also significantly decreased the bacterial load in the spleen and liver compared to those of the controls. Our study reports, for the first time, the protective roles of theEhrlichiaP28-9 and P28-12 proteins in addition to confirming previous reports of the protective ability of P28-19. Partial protection induced by immunization with P28-9, P28-12, and P28-19 againstEhrlichiawas associated with the generation ofEhrlichia-specific cell-mediated and humoral immune responses.

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