scholarly journals Establishment of Chronic Typhoid Infection in a Mouse Carriage Model Involves a Type 2 Immune Shift and T and B Cell Recruitment to the Gallbladder

mBio ◽  
2019 ◽  
Vol 10 (5) ◽  
Author(s):  
Juan F. González ◽  
Jonathan Kurtz ◽  
David L. Bauer ◽  
Regan Hitt ◽  
James Fitch ◽  
...  
Keyword(s):  
T Cells ◽  
Inflammatory Response ◽  
Salmonella Enterica ◽  
Systemic Disease ◽  
Interleukin 4 ◽  
Th2 Response ◽  
Content Type ◽  
Chronic Carriage ◽  
Anti Inflammatory

ABSTRACT Typhoid fever, caused primarily by Salmonella enterica serovar Typhi (S. Typhi), is a life-threatening systemic disease responsible for significant morbidity and mortality worldwide. Three to 5% of individuals infected with S. Typhi become chronic carriers due to bacterial persistence in the gallbladder. We have demonstrated that Salmonella forms biofilms on gallstones to establish gallbladder carriage. However, an in-depth molecular understanding of chronic carriage in the gallbladder, from the perspective of both the pathogen and host, is poorly defined. To examine the dynamics of the gallbladder in response to Salmonella infection, we performed transcriptional profiling in the mouse gallbladder at early (7 days) and chronic (21 days) time points. Transcriptome sequencing (RNA-Seq) revealed a shift from a Th1 proinflammatory response at 7 days postinfection (dpi) toward an anti-inflammatory Th2 response by 21 dpi, characterized by increased levels of immunoglobulins and the Th2 master transcriptional regulator, GATA3. Additionally, bioinformatic analysis predicted the upstream regulation of characteristic Th2 markers, including interleukin-4 (IL-4) and Stat6. Immunohistochemistry and fluorescence-activated cell sorter (FACS) analysis confirmed a significant increase in lymphocytes, including T and B cells, at 21 dpi in mice with gallstones. Interestingly, the levels of Salmonella-specific CD4 T cells were 10-fold higher in the gallbladder of mice with gallstones at 21 dpi. We speculate that the biofilm state allows Salmonella to resist the initial onslaught of the Th1 inflammatory response, while yet undefined events influence a switch in the host immunity toward a more permissive type 2 response, enabling the establishment of chronic infection. IMPORTANCE The existence of chronic typhoid carriers has been in the public eye for over 100 years in part because of the publicity around Typhoid Mary. Additionally, it has been known for decades that the gallbladder is the main site of persistence and recently that gallstones play a key role. Despite this, very little is known about the physiological conditions that allow Salmonella enterica serovar Typhi to persist in the gallbladder. In this study, we analyze the transcriptional profile of the gallbladder in a mouse model of chronic carriage. We found a shift from an early proinflammatory immune response toward a later anti-inflammatory response, which could explain the stalemate that allows Salmonella persistence. Interestingly, we found a 10-fold increase in the number of Salmonella-specific T cells in mice with gallstones. This work moves us closer to understanding the mechanistic basis of chronic carriage, with a goal toward eradication of the disease.

scholarly journals Transgenic Expression of CXCR3 on T Cells Enhances Susceptibility to Cutaneous Leishmania major Infection by Inhibiting Monocyte Maturation and Promoting a Th2 Response

2014 ◽  
Vol 83 (1) ◽  
pp. 67-76 ◽  
Author(s):  
Steve Oghumu ◽  
James C. Stock ◽  
Sanjay Varikuti ◽  
Ran Dong ◽  
Cesar Terrazas ◽  
...  
Keyword(s):  
T Cells ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Major ◽  
Critical Role ◽  
Sand Fly ◽  
Interleukin 4 ◽  
Th2 Response ◽  
Content Type ◽  
Transgenic Expression ◽  
Inflammatory Monocytes

Cutaneous leishmaniasis, caused mainly byLeishmania major, an obligate intracellular parasite, is a disfiguring disease characterized by large skin lesions and is transmitted by a sand fly vector. We previously showed that the chemokine receptor CXCR3 plays a critical role in mediating resistance to cutaneous leishmaniasis caused byLeishmania major. Furthermore, T cells fromL. major-susceptible BALB/c but notL. major-resistant C57BL/6 mice fail to efficiently upregulate CXCR3 upon activation. We therefore examined whether transgenic expression of CXCR3 on T cells would enhance resistance toL. majorinfection in susceptible BALB/c mice. We generated BALB/c and C57BL/6 transgenic mice, which constitutively overexpressed CXCR3 under a CD2 promoter, and then examined the outcomes withL. majorinfection. Contrary to our hypothesis, transgenic expression of CXCR3 (CXCR3Tg) on T cells of BALB/c mice resulted in increased lesion sizes and parasite burdens compared to wild-type (WT) littermates afterL. majorinfection. Restimulated lymph node cells fromL. major-infected BALB/c-CXCR3Tgmice produced more interleukin-4 (IL-4) and IL-10 and less gamma interferon (IFN-γ). Cells in draining lymph nodes from BALB/c-CXCR3Tgmice showed enhanced Th2 and reduced Th1 cell accumulation associated with increased neutrophils and inflammatory monocytes. However, monocytes displayed an immature phenotype which correlated with increased parasite burdens. Interestingly, transgenic expression of CXCR3 on T cells did not impact the outcome ofL. majorinfection in C57BL/6 mice, which mounted a predominantly Th1 response and spontaneously resolved their infection similar to WT littermates. Our findings demonstrate that transgenic expression of CXCR3 on T cells increases susceptibility of BALB/c mice toL. major.

scholarly journals Repeated Exposure to Aspergillus fumigatus Conidia Results in CD4+T Cell-Dependent and -Independent Pulmonary Arterial Remodeling in a Mixed Th1/Th2/Th17 Microenvironment That Requires Interleukin-4 (IL-4) and IL-10

2011 ◽  
Vol 80 (1) ◽  
pp. 388-397 ◽  
Author(s):  
Andrew B. Shreiner ◽  
Benjamin J. Murdock ◽  
Amir A. Sadighi Akha ◽  
Nicole R. Falkowski ◽  
Paul J. Christensen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Aspergillus Fumigatus ◽  
Pulmonary Arteries ◽  
Interleukin 4 ◽  
Arterial Remodeling ◽  
Th2 Response ◽  
Content Type ◽  
Inflammatory Microenvironment ◽  
Pulmonary Arterial

ABSTRACTPulmonary arterial remodeling is a pathological process seen in a number of clinical disease states, driven by inflammatory cells and mediators in the remodeled artery microenvironment. In murine models, Th2 cell-mediated immune responses to inhaled antigens, such as purifiedAspergillusallergen, have been reported to induce remodeling of pulmonary arteries. We have previously shown that repeated intranasal exposure of healthy C57BL/6 mice to viable, restingAspergillus fumigatusconidia leads to the development of chronic pulmonary inflammation and the coevolution of Th1, Th2, and Th17 responses in the lungs. Our objective was to determine whether repeated intranasal exposure toAspergillusconidia would induce pulmonary arterial remodeling in this mixed Th inflammatory microenvironment. Using weekly intranasal conidial challenges, mice developed robust pulmonary arterial remodeling after eight exposures (but not after two or four). The process was partially mediated by CD4+T cells and by interleukin-4 (IL-4) production, did not require eosinophils, and was independent of gamma interferon (IFN-γ) and IL-17. Furthermore, remodeling could occur even in the presence of strong Th1 and Th17 responses. Rather than serving an anti-inflammatory function, IL-10 was required for the development of the Th2 response toA. fumigatusconidia. However, in contrast to previous studies of pulmonary arterial remodeling driven by theA. fumigatusallergen, viable conidia also stimulated pulmonary arterial remodeling in the absence of CD4+T cells. Remodeling was completely abrogated in IL-10−/−mice, suggesting that a second, CD4+T cell-independent, IL-10-dependent pathway was also driving pulmonary arterial remodeling in response to repeated conidial exposure.

scholarly journals Identification of Two Distinct Subpopulations of Leishmania major-Specific T Helper 2 Cells

2002 ◽  
Vol 70 (10) ◽  
pp. 5512-5520 ◽  
Author(s):  
Pascale Kropf ◽  
Shanti Herath ◽  
Rita Tewari ◽  
Nelofer Syed ◽  
Roman Klemenz ◽  
...  
Keyword(s):  
T Cells ◽  
Leishmania Major ◽  
Lymphoid Organs ◽  
Cytokine Profile ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Th2 Response ◽  
T Helper 2

ABSTRACT It is widely accepted that a strong Th2 response is responsible for nonhealing Leishmania major infections in BALB/c mice. This Th2 response has been thoroughly documented by measuring the levels of Th2 cytokines produced by CD4+ T cells present in the lymphoid organs by enzyme-linked immunosorbent assay and PCR. However, the cytokine profile of L. major-specific Th2 cells has never been determined. In this study, we used the recently described Th2 marker T1/ST2 to characterize Th2 cells during the course of nonhealing L. major infection. We analyzed the intracellular cytokine profile of CD4+ T1/ST2+ T cells and showed that they clearly displayed a Th2 phenotype, as they expressed interleukin 4 (IL-4), IL-10, and IL-5. In addition, we detected another population of Th2 cells among the CD4+ T1/ST2− T cells that expressed IL-4 and IL-10 but excluded IL-5. In summary, we show here that two type 2 subpopulations are present in the lymphoid organs of L. major-infected BALB/c mice; Th2 cells from both subsets expressed IL-4 and IL-10, but they could be distinguished by their expression of IL-5 and T1/ST2.

scholarly journals Effect of Orally AdministeredAtractylodes macrocephalaKoidz Water Extract on Macrophage and T Cell Inflammatory Response in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Tae-Kyung Kwak ◽  
Hyung-Seok Jang ◽  
Mi-Gi Lee ◽  
Young-Sung Jung ◽  
Dae-Ok Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Response ◽  
T Cell Activation ◽  
Inflammatory Responses ◽  
Water Extract ◽  
Peritoneal Macrophages ◽  
Functional Responses ◽  
Th2 Response ◽  
Anti Inflammatory

The rhizome ofAtractylodes macrocephalaKoidz (AM) is a constituent of various Qi booster compound prescriptions. We evaluated inflammatory responses in macrophages and T cells isolated from mice following oral administration of AM water extract (AME). Peritoneal exudate cells were isolated from thioglycollate-injected mice and alterations in scavenger receptors were examined. Peritoneal macrophages were stimulated with lipopolysaccharide (LPS). Serum cytokine responses to intraperitoneal LPS injection were also evaluated. Splenocytes were isolated and their composition and functional responses were measured. The content of atractylenolide I and atractylenolide III, known anti-inflammatory ingredients, in AME was 0.0338 mg/g extract and 0.565 mg/g extract, respectively. AME increased the number of SRA(+)CD11b(+) cells in response to thioglycollate. Peritoneal macrophages isolated from the AME group showed no changes in inflammatory markers such as tumor necrosis factor- (TNF-)α, interleukin- (IL-) 6, inducible nitric oxide synthase, and cyclooxygenase-2 but exhibited a decrease in CD86 expression. Interestingly, AME decreased the serum levels of TNF-αand IL-6 upon intraperitoneal injection of LPS. Regarding the adaptive immune system, AME increased the CD4(+) T cell population and major histocompatibility complex class II molecule expression in the spleen, and cultured splenocytes from the AME group showed increased production of IL-4 concurrent with decreased interferon-γproduction during T cell activation. AME promoted the replenishment of peritoneal macrophages during the inflammatory response but its anti-inflammatory activity did not appear to be mediated by the modulation of macrophage activity. AME also altered the immune status of CD4 T cells, promoting the Th2 response.

scholarly journals The Invasion Plasmid Antigen J (IpaJ) from Salmonella Inhibits NF-κB Activation by Suppressing IκBα Ubiquitination

2019 ◽  
Vol 88 (3) ◽  
Author(s):  
Qiuchun Li ◽  
Lijuan Xu ◽  
Chao Yin ◽  
Zijian Liu ◽  
Yang Li ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Proinflammatory Cytokines ◽  
Hela Cells ◽  
Salmonella Enterica ◽  
Systemic Infection ◽  
Peripheral Blood Monocyte ◽  
Effector Proteins ◽  
Economic Losses ◽  
Necrosis Factor Alpha ◽  
Content Type

ABSTRACT Salmonella enterica serovar Pullorum is the pathogen of pullorum disease, which leads to severe economic losses in many developing countries. In contrast to the strong inflammatory response induced by Salmonella enterica serovar Typhimurium and Salmonella enterica serovar Enteritidis, S. Pullorum causes systemic infection with little inflammation. The effector proteins secreted by Salmonella often play a crucial role in modulating host signal transduction and cellular processes to the pathogen’s advantage. In the present study, the invasion plasmid antigen J (IpaJ) protein specifically identified in S. Pullorum was found to significantly inhibit activation of the key proinflammatory transcription factor, NF-κB, which was induced by tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and lipopolysaccharide (LPS). IpaJ inhibited the NF-κB pathway in cells infected with S. Pullorum through the stabilization of IκBα. Deletion of ipaJ in S. Pullorum caused a significantly increased level of ubiquitinated IκBα that was subsequently degraded by the proteasome in HeLa cells. Moreover, IpaJ was efficient in the prevention of NF-κB translocation to the nucleus and ultimately interfered with the secretion of the proinflammatory cytokines IL-1β, IL-6, and IL-8 in infected HeLa cells. Additionally, the transformation of ipaJ into S. Enteritidis decreased the secretion of proinflammatory cytokines in HeLa cells through suppression of the NF-κB pathway. The infection of chicken peripheral blood monocyte-derived macrophages (chMDM) confirmed that ipaJ-deleted S. Pullorum induced a stronger expression of proinflammatory cytokines than the wild-type and complementary strains. In summary, the present study revealed that IpaJ functions as an important anti-inflammatory protein involved in S. Pullorum infection through inhibition of the NF-κB pathway and the subsequent inflammatory response.

scholarly journals Clinical and Immune Impact of Mycobacterium bovis BCG Vaccination Scarring

2002 ◽  
Vol 70 (11) ◽  
pp. 6188-6195 ◽  
Author(s):  
Janine Jason ◽  
Lennox K. Archibald ◽  
Okey C. Nwanyanwu ◽  
Peter N. Kazembe ◽  
Julie A. Chatt ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Bovis ◽  
Clinical Symptoms ◽  
Surrogate Marker ◽  
Bcg Vaccine ◽  
World Health ◽  
Interleukin 4 ◽  
Bcg Vaccination ◽  
Cytokine Pattern

ABSTRACT The World Health Organization recommends Mycobacterium bovis BCG vaccination in areas of high tuberculosis prevalence. BCG's clinical and immune effects, not necessarily Mycobacterium tuberculosis specific, are unclear. BCG vaccine scarring often is used as a surrogate marker of vaccination or of effective vaccination. We evaluated BCG scarring status in relation to clinical findings and outcome in 700 hospitalized Malawians, of whom 32 had M. tuberculosis bloodstream infections (BSI) (10 of whom had cellular immune studies done) and of whom 48 were infants <6 months old and therefore recently vaccinated (19 of whom had immune studies). In the patients ≥6 months old, scarring was not related to the presence of pulmonary symptoms (35 versus 30%), chronic cough or fever, mortality, or M. tuberculosis BSI. In M. tuberculosis BSI patients, scarring was unrelated to mortality, vital signs, or clinical symptoms but those with scarring had higher proportions of memory and activated T cells and more type 2-skewed cytokine profiles. Infants with either BCG scarring (n = 10) or BCG lesional inflammation (n = 5) had no symptoms of sepsis, but 18 of 33 infants without BCG vaccination lesions did. Those with BCG lesions had localized infections more often than did those without BCG lesions. These infants also had lower median percentages of lymphocytes spontaneously making interleukin-4 (IL-4) or tumor necrosis factor alpha (TNF-α) and lower ratios of T cells spontaneously making IL-4 to T cells making IL-6. Thus, we found that, in older patients, BCG vaccine scarring was not associated with M. tuberculosis-specific or nonspecific clinical protection. Those with M. tuberculosis BSI and scarring had immune findings suggesting previous M. tuberculosis antigen exposure and induction of a type 2 cytokine pattern with acute reexposure. It is unlikely that this type 2 pattern would be protective against mycobacteria, which require a type 1 response for effective containment. In infants <6 months old, recent BCG vaccination was associated with a non-M. tuberculosis-specific, anti-inflammatory cytokine profile. That the vaccinated infants had a greater frequency of localized infections and lesser frequency of sepsis symptoms suggests that this postvaccination cytokine pattern may provide some non-M. tuberculosis-specific clinical benefits.

scholarly journals Oxazolone Colitis: A Murine Model of  T Helper Cell Type 2 Colitis Treatable with Antibodies to Interleukin 4

1998 ◽  
Vol 188 (10) ◽  
pp. 1929-1939 ◽  
Author(s):  
Monica Boirivant ◽  
Ivan J. Fuss ◽  
Alan Chu ◽  
Warren Strober
Keyword(s):  
T Cells ◽  
Transforming Growth Factor ◽  
Fold Increase ◽  
T Helper Cell ◽  
Interleukin 4 ◽  
Helper Cell ◽  
Cell Type ◽  
T Helper ◽  
Helper Cell Type

In this study we describe oxazolone colitis, a new form of experimental colitis. This model is induced in SJL/J mice by the rectal instillation of the haptenating agent, oxazolone, and is characterized by a rapidly developing colitis confined to the distal half of the colon; it consists of a mixed neutrophil/lymphocyte infiltration limited to the superficial layer of the mucosa which is associated with ulceration. Oxazolone colitis is a T helper cell type 2 (Th2)-mediated process since stimulated T cells from lesional tissue produce markedly increased amounts of interleukin (IL)-4 and IL-5; in addition, anti–IL-4 administration leads to a striking amelioration of disease, whereas anti–IL-12 administration either has no effect or exacerbates disease. Finally, this proinflammatory Th2 cytokine response is counterbalanced by a massive transforming growth factor-β (TGF-β) response which limits both the extent and duration of disease: lesional (distal) T cells manifest a 20–30-fold increase in TGF-β production, whereas nonlesional (proximal) T cells manifest an even greater 40–50-fold increase. In addition, anti–TGF-β administration leads to more severe inflammation which now involves the entire colon. The histologic features and distribution of oxazolone colitis have characteristics that resemble ulcerative colitis (UC) and thus sharply distinguish this model from most other models, which usually resemble Crohn's disease. This feature of oxazolone colitis as well as its cytokine profile have important implications to the pathogenesis and treatment of UC.

scholarly journals Increased Persistence of Salmonella enterica Serovar Typhi in the Presence of Acanthamoeba castellanii

2011 ◽  
Vol 77 (21) ◽  
pp. 7640-7646 ◽  
Author(s):  
Frédéric Douesnard-Malo ◽  
France Daigle
Keyword(s):  
Salmonella Enterica ◽  
Pathogenic Bacteria ◽  
Systemic Disease ◽  
Acanthamoeba Castellanii ◽  
Selective Advantage ◽  
Viable Count ◽  
Physical Contact ◽  
Content Type ◽  
Contaminated Food ◽  
Cultured Bacteria

ABSTRACTSalmonella entericaserovar Typhi (S. Typhi) is the etiological agent of the systemic disease typhoid fever. Transmission occurs via ingestion of contaminated food or water.S. Typhi is specific to humans, and no animal or environmental reservoirs are known. As the free-living amoebaAcanthamoeba castellaniiis an environmental host for many pathogenic bacteria, this study investigates interactions betweenS. Typhi andA. castellaniiby using cocultures. Growth of both organisms was estimated by cell count, viable count, flow cytometry, and fluorescence microscopy. Results indicate thatS. Typhi can survive at least 3 weeks when grown withA. castellanii, as opposed to less than 10 days when grown as singly cultured bacteria under the same conditions. Interestingly, growth rates of amoebae after 14 days were similar in cocultures or when amoebae were singly cultured, suggesting thatS. Typhi is not cytotoxic toA. castellanii. Bacteria surviving in coculture were not intracellular and did not require a physical contact with amoebae for their survival. These results suggest thatS. Typhi may have a selective advantage when it is associated withA. castellaniiand that amoebae may contribute toS. Typhi persistence in the environment.

scholarly journals Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells.

1995 ◽  
Vol 182 (5) ◽  
pp. 1591-1596 ◽  
Author(s):  
S Constant ◽  
C Pfeiffer ◽  
A Woodard ◽  
T Pasqualini ◽  
K Bottomly
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Functional Differentiation ◽  
Interleukin 4 ◽  
Cell Mediated Immunity ◽  
Receptor Ligation

Naive CD4+ T cells can differentiate into cells predominantly involved in humoral immunity, known as T helper type 2 cells (Th2), or cells involved in cell-mediated immunity, known as Th1 cells. In this report, we show that priming of CD4+ T cells bearing a transgene-encoded T cell receptor can lead to differentiation into Th1-like cells producing abundant interferon gamma when the cells are exposed to high antigen doses, while low doses of the same peptide induce cells with the same T cell receptor to differentiate into Th2-like cells producing abundant interleukin 4. Thus antigen dose is one factor that can control the differentiation fate of a naive CD4+ T cell.

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