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1.
The host immune response to infection with Mycobacterium paratuberculosis is paradoxical, with strong cell-mediated immune responses during the early, subclinical stages of infection and strong humoral responses during the late clinical stages of the disease. Cell-mediated immune responses modulated by various T cell subsets are essential to provide protective immunity and prevent progression of the disease. Secretion of cytokines by T cell populations serves to activate macrophages to kill ingested M. paratuberculosis as well as activate other T cell subsets to contain the infection. This paper reviews the current knowledge of T cell immune responses in M. paratuberculosis infection based upon clinical studies and research using mouse models.  相似文献   

2.
Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) is the causative agent of Johne's disease, a deadly intestinal ailment of ruminants. Johne's disease is of tremendous economic importance to the worldwide dairy industry, causing major losses due to reduced production and early culling of animals. A highly controversial but developing link between exposure to M. paratuberculosis and human Crohn's disease in some individuals has led to the suggestion that M. paratuberculosis is also a potential food safety concern. As with many other mycobacteria, M. paratuberculosis is exquisitely adapted to survival in the host, despite aggressive immune reactions to these organisms. One hallmark of mycobacteria, including M. paratuberculosis, is their propensity to infect macrophages. Inside the macrophage, M. paratuberculosis interferes with the maturation of the phagosome by an unknown mechanism, thereby evading the host's normal first line of defense against bacterial pathogens. The host immune system begins a series of attacks against M. paratuberculosis-infected macrophages, including the rapid deployment of activated gammadelta T cells, CD4+ T cells and cytolytic CD8+ T cells. These cells interact with the persistently infected macrophage and with each other through a complex network of cytokines and receptors. Despite these aggressive efforts to clear the infection, M. paratuberculosis persists and the constant struggle of the immune system leads to pronounced damage to the intestinal epithelial cells. Enhancing our ability to control this important and tenacious pathogen will require a deeper understanding of how M. paratuberculosis interferes with macrophage action, the cell types involved in the immune response, the cytokines these cells use to communicate, and the host genetic factors that control the response to infection.  相似文献   

3.
Invading pathogens are controlled by the innate and adaptive arms of the immune system. Adaptive immunity, mediated by B and T lymphocytes, recognises pathogens via high affinity receptors. However, the establishment of a primary adaptive immune response is not rapid enough to eradicate invading microorganisms as it involves cell proliferation, gene activation and protein synthesis. More rapid defence mechanisms are provided by innate immunity, which recognises invading pathogens by germ-line-encoded pattern recognition receptors. Recent evidence shows that this recognition can mainly be attributed to the family of TOLL-like receptors (TLR). Binding of pathogen-associated molecular patterns to TLR induces the production of reactive oxygen and nitrogen intermediates, pro-inflammatory cytokines, and up-regulates expression of co-stimulatory molecules, subsequently initiating the adaptive immunity. In this paper, we will discuss the current knowledge with regards to the TLR, and in particular the bovine family of TLR. In addition, we will show the expression of TLR mRNA in bovine antigen-presenting cell subsets, summarise the discovery and the critical roles of TLR2 in host defence against Mycobacteria, and provide evidence for a mycobacteria species-specific response of bovine macrophages.  相似文献   

4.
TOLL-like receptors linking innate and adaptive immune response   总被引:25,自引:0,他引:25  
Invading pathogens are controlled by the innate and adaptive arms of the immune system. Adaptive immunity, which is mediated by B and T lymphocytes, recognises pathogens by rearranged high affinity receptors. However, the establishment of adaptive immunity is often not rapid enough to eradicate microorganisms as it involves cell proliferation, gene activation and protein synthesis. More rapid defense mechanisms are provided by innate immunity, which recognises invading pathogens by germ-line-encoded pattern recognition receptors (PRR). Recent evidence shows that this recognition can mainly be attributed to the family of TOLL-like receptors (TLR). Binding of pathogen-associated molecular patterns (PAMP) to TLR induces the production of reactive oxygen and nitrogen intermediates (ROI and RNI), pro-inflammatory cytokines, and up-regulates expression of co-stimulatory molecules, subsequently initiating the adaptive immunity. In this review, we will summarize the discovery and the critical roles of the TLR family in host defense, briefly allude to signaling mechanisms mediating the response to TLR ligands, and will provide an update on current knowledge regarding the ligand specificity of these receptors and their role in immunity of domestic animals, particularly cattle.  相似文献   

5.
皮肤和黏膜上皮细胞既是机体的物理屏障,又是机体防御微生物的第一道防线。上皮细胞与白细胞、树突细胞(DCs)等之间的相互作用,是机体产生适应性免疫反应的重要因素。IL-17细胞因子家族是最近新发现的具有强大的促炎症作用的细胞因子,它们在机体的固有和适应性免疫中发挥着重要作用,IL-17A、IL-17C和IL-17F能够直接作用于组织的上皮细胞,诱导各种免疫反应来对抗病原体,且能够促进组织的修复。IL-17E最基本的作用是作用于白细胞和诱导Ⅱ型免疫,这在其对抗寄生虫的作用中是非常关键的,此外,IL-17E还可以反向调节白细胞对IL-17A和IL-17F的产生;而对于IL-17B和IL-17D的研究则相对较少一些。  相似文献   

6.
Streptococcus uberis and Serratia marcescens are Gram-positive and Gram-negative bacteria, respectively, that induce clinical mastitis. Once initial host barrier systems have been breached by these pathogens, the innate immune system provides the next level of defense against these infectious agents. The innate immune response is characterized by the induction of pro-inflammatory cytokines, as well as increases in other accessory proteins that facilitate host recognition and elimination of the pathogens. The objective of the current study was to characterize the innate immune response during clinical mastitis elicited by these two important, yet less well-studied, Gram-positive and Gram-negative organisms. The pro-inflammatory cytokine response and changes in the levels of the innate immune accessory recognition proteins, soluble CD14 (sCD14) and lipopolysaccharide (LPS)-binding protein (LBP), were studied. Decreased milk output, induction of a febrile response, and increased acute phase synthesis of LBP were all characteristic of the systemic response to intramammary infection with either organism. Infection with either bacteria similarly resulted in increased milk levels of IL-1 beta, IL-8, IL-10, IL-12, IFN-gamma, TNF-alpha, sCD14, LBP, and the complement component, C5a. However, the duration of and/or maximal changes in the increased levels of these inflammatory markers were significantly different for several of the inflammatory parameters assayed. In particular, S. uberis infection was characterized by the sustained elevation of higher milk levels of IL-1 beta, IL-10, IL-12, IFN-gamma, and C5a, relative to S. marcescens infection. Together, these data demonstrate the variability of the innate immune response to two distinct mastitis pathogens.  相似文献   

7.
In contrast to other mastitis pathogens, the host response evoked during Staphylococcus aureus intramammary infection is marked by the absence of the induction of critical cytokines, including IL-8 and TNF-alpha, which have established roles in mediating host innate immunity. The elucidation of changes in the expression of other mediators with the potential to regulate mammary inflammatory responses to S. aureus remains lacking. Transforming growth factor (TGF)-alpha, TGF-beta1, and TGF-beta2 are cytokines that regulate mammary gland development. Because these cytokines also have a demonstrated role in mediating inflammation, the objective of the current study was to determine whether S. aureus intramammary infection influences their expression. Ten cows were challenged with S. aureus and milk samples collected. Increases in milk levels of TGF-alpha were evident within 32h of infection and persisted for 16h. Increases in TGF-beta1 and TGF-beta2 levels were detected within 40h of S. aureus infection and persisted through the end of the study. Thus, in contrast to IL-8 and TNF-alpha, S. aureus elicits host production of TGF-alpha, TGF-beta1, and TGF-beta2. This finding may suggest a role for these cytokines in mediating mammary gland host innate immune responses to S. aureus.  相似文献   

8.
Johne's disease progresses through distinct stages including a protracted subclinical stage in which the infection appears to be controlled; followed by a more acute stage in which the host animal demonstrates clinical signs such as diarrhea and weight loss. Little is known about the dynamics of the host immune response during these two phases of disease, however, it is possible that immune modulation in the early stages of disease may play an important role in disease progression. We hypothesized that the clinical stage of Johne's disease is mediated by the expression of cytokines such as transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) that may be accompanied by the downregulation of IFN-gamma gene expression. In the present study, tissue samples were collected from the ileum, ileocecal junction, ileocecal lymph node, and mesenteric lymph nodes of healthy, subclinically or clinically infected cows. The expression of TGF-beta, IL-10, and IFN-gamma genes in these tissues was determined by quantitative competitive RT-PCR. The results demonstrate that TGF-beta and IL-10 mRNA levels are higher in cows that have progressed to the clinical stage of disease compared to subclinically infected or healthy cows. In contrast, IFN-gamma gene expression was significantly higher in subclinically infected cows. These results suggest that a change in the balance of cytokines at the site of infection may contribute to the ability of the host to control Mycobacterium avium subsp. paratuberculosis infection.  相似文献   

9.
The GroES antigen provokes a strong immune response in human beings with tuberculosis or leprosy. We cloned and sequenced the Mycobacterium avium and Mycobacterium paratuberculosis GroES genes. M. avium and M. paratuberculosis have identical GroES sequences which differ from other mycobacterial species. This supports the current formal designation of M. paratuberculosis as M. avium subsp. paratuberculosis. Immunodominant epitopes from Mycobacterium tuberculosis GroES are conserved in M. avium, but some Mycobacterium leprae epitopes are distinct. GroES is unlikely to be specific as a serologic or skin test reagent, but may be an appropriate component of a broad mycobacterial vaccine.  相似文献   

10.
Bovine paratuberculosis is characterized by a chronic inflammation of the small intestine, caused by infection with Mycobacterium avium ssp. paratuberculosis. Research regarding diagnostic as well as immunopathogenic aspects of paratuberculosis are hampered by the lack of specific antigens. The aim of the present study was to evaluate the potential of mycobacterial heat-shock proteins, as specific antigens, to measure cell-mediated immune responses during various stages of the disease. In a cross-sectional study, peripheral blood mononuclear cells of 179 cows in different stages of M. avium ssp. paratuberculosis infection, vaccinated against paratuberculosis or noninfected, were used to evaluate lymphoproliferative responses to mycobacterial heat-shock protein of 70 kD (HSP70) and 65 kD (HSP65). In addition, lymphoproliferative responses were measured using purified protein derivate (PPD) preparations from M. avium ssp. paratuberculosis, M. avium and M. bovis as antigens. Responses to HSP70 were higher in the vaccinated animals and in asymptomatic animals that shed the organism in their faeces. Compared with these animals, responses were lower in cows with clinical signs of paratuberculosis. Mycobacterial HSP65 induced less prominent responses compared with HSP70, but showed a similar pattern with regard to the stages of disease. Vaccinated and shedding animals also showed the highest responses to PPD derived from M. avium ssp. paratuberculosis (PPD-P). Observations with short-term cell lines raised to PPD-P and to HSP70 indicated that the similarity between those two antigens was not due to the presence of HSP70 in PPD-P. In conclusion, our study indicated that, as for PPD antigens the mycobacterial heat-shock protein-specific cell-mediated immune responses decrease when comparing the asymptomatic stage to the clinical stage in bovine paratuberculosis. Furthermore, this study shows that HSP70, being a well-defined antigen in comparison with PPD antigens, can be used to monitor cell-mediated immune responses in studies regarding the immunopathogenesis of bovine paratuberculosis.  相似文献   

11.
Paratuberculosis or Johne's disease of livestock, which is caused by Mycobacterium avium subsp. paratuberculosis (MAP), has increased in prevalence and expanded in geographic and host ranges over about 100 years. The slow and progressive spread of MAP reflects its substantial adaptation to its hosts, the technical limitations of diagnosis, the lack of practical therapeutic approaches, the lack of a vaccine that prevents transmission and the complexity and difficulty of the on-farm control strategies needed to prevent infection. More recently evidence has accumulated for an association of MAP with Crohn's disease in humans, adding to the pressure on animal health authorities to take precautions by controlling paratuberculosis. Mycobacterial infections invoke complex immune responses but the essential determinants of virulence and pathogenesis are far from clear. In this review we compare the features of major diseases in humans and animals that are caused by the pathogenic mycobacteria M. ulcerans, M. avium subsp. avium, M. leprae, M. tuberculosis and MAP. We seek to answer key questions: are the common mycobacterial infections of humans and animals useful "models" for each other, or are the differences between them too great to enable meaningful extrapolation? To simplify this, the immunopathogenesis of mycobacterial infections will be defined at cellular, tissue, animal and population levels and the key events at each level will be discussed. Many pathogenic processes are similar between divergent mycobacterial diseases, and at variance between virulent and avirulent isolates of mycobacteria, suggesting that the research on the pathogenesis of one mycobacterial disease will be informative for the others.  相似文献   

12.
Almost half of all clinical cases of mastitis are caused by Gram-negative bacteria. Among these bacteria, intramammary infection by Pseudomonas aeruginosa remains one of the most refractory to antibiotic therapy. The ability to recognize potentially harmful pathogens whether previously encountered or not, as well as the induction of an initial pro-inflammatory response to these pathogens, are critical components of host innate immunity. Although the innate immune response to another Gram-negative mastitis-causing pathogen, Escherichia coli, has been well-characterized, little is known about the response to other Gram-negative bacteria, including P. aeruginosa. The objective of the current study was to characterize the systemic and localized bovine innate immune response to intramammary infection with P. aeruginosa. The contralateral quarters of ten mid-lactating Holstein cows were challenged with either saline or P. aeruginosa. Following the establishment of infection, milk samples were collected and assayed for changes in cytokine and growth factor concentrations, complement activation, and changes in the levels of soluble CD14 (sCD14) and lipopolysaccharide (LPS)-binding protein (LBP), two accessory molecules involved in host recognition of Gram-negative bacteria. Initial increases in milk somatic cell counts were evident within 12h of experimental challenge and remained elevated for >or=3 weeks. Increased permeability of the mammary gland vasculature, as evidenced by elevated milk levels of BSA, was initially observed 20 h post-infection and persisted for 2 weeks. Within 32 h of challenge, increased levels of IL-8, TNF-alpha, IL-10, and IL-12 were detected, however, the elevated levels of these cytokines were not sustained for longer than a 24h period. In contrast, elevations in IL-1beta, IFN-gamma, TGF-alpha, TGF-beta1, TGF-beta2, sCD14, LBP, and activated complement factor 5 (C5a) were sustained for periods of >48 h. Systemic changes were characterized by elevated body temperature, induction of the acute phase protein synthesis of serum amyloid A and LBP, and a transient decrease in circulating neutrophils and lymphocytes. Together, these data demonstrate the capability of the mammary gland to mount a robust innate immune response to P. aeruginosa that is characterized by the induction of pro-inflammatory cytokines, complement activation, and increased levels of accessory molecules involved in Gram-negative bacterial recognition.  相似文献   

13.
Mycobacterium paratuberculosis is the causative agent of paratuberculosis (Johne's disease), a chronic inflammation of the terminal portion of the ileum in ruminants. The predominance of cell-mediated immunity in early stages of the disease suggests that T lymphocytes are essential to protect the host from infection with M. paratuberculosis. In this study, we investigated the role of alphabeta and gammadelta T cells in resistance to M. paratuberculosis infection using a T-cell receptor (TCR) knockout mouse model. Weanling TCR-alpha-deficient, TCR-delta-deficient, and C57BL/6 control mice (5-6 weeks of age) were acclimated for 2 weeks and then inoculated intraperitoneally with 10(8)CFU/ml of M. paratuberculosis (either strain 19698 or strain Ben). Groups of mice within each treatment group were euthanized at 1, 3 and 6 months post-inoculation. Sections of spleen, liver, ileum and mesenteric lymph node were prepared for bacterial culture and histologic examination. At all time points of infection and regardless of bacterial strain, TCR-alpha-deficient mice had higher levels of M. paratuberculosis colonization in their tissues compared to TCR-delta-deficient mice or C57BL/6 control mice. Lesions were located predominately in the liver and the ileum, depending upon period of infection, and lesion scores were higher for TCR-alpha-deficient mice compared to the other treatment groups. These results suggest that alphabeta T cells play a major role in resistance to infection with M. paratuberculosis and that gammadelta T cells may play a lesser role and potentially confound protective immune responses.  相似文献   

14.
15.
The initial suggestion that Mycobacterium avium subsp. paratuberculosis (Map) might be involved in the pathogenesis of Crohn's disease (CD) was based on the apparent similarity of lesions in the intestine of patients with CD with those present in cattle infected with Map, the etiological agent of Johne's disease (JD). Recent investigations have now revealed the presence of Map or Map DNA in blood or lesions from adults and children with CD. Of special interest, Map has also been found in patients with other diseases as well as healthy subjects. The latter observations indicate all humans are susceptible to infection with Map and that, like with other mycobacterial pathogens such as Mycobacterium tuberculosis, infection does not invariably lead to development of clinical disease but rather development of a persistent latent stage of infection where an immune response controls but does not eliminate the pathogen. Limited information has been obtained on the immune response to Map in healthy subjects and patients with CD. Understanding how Map may be involved in the pathogenesis of CD will require a better understanding of the immune response to Map in one of its common hosts as well as healthy humans and patients with CD.  相似文献   

16.
The role of gamma(delta) T cells in the bovine immune response to Mycobacterium avium subsp. paratuberculosis (M. paratuberculosis) infection is poorly understood. Accordingly, using BALB/c mice that are innately susceptible to M. paratuberculosis, we compared wild-type and gamma(delta) T cell knockout BALB/c mice to study the protective roles of gamma(delta) T cells in M. paratuberculosis infection. Ten-week-old mice were inoculated intraperitoneally with either a low dose (4 x 10(6) colony-forming units [CFU]/mouse) or a high dose (4 x 10(9) CFU/mouse) of M. paratuberculosis strain ATCC 19698. Histopathologic and morphometric examinations showed reductions in the number and area of granulomatous lesions in the liver of the knockout mice at 18 weeks after inoculation with either the low or the high dose of the mycobacteria. Furthermore, at 18 weeks after inoculation, the bacterial load in the spleens of the knockout mice inoculated with the high dose was significantly lower than that of wild-type mice. No differences were found in bacterial load between the knockout and the wild-type mice in the low-dose groups. In contrast, in the livers of wild-type mice inoculated with either the low or high mycobacterial dose, increased areas of epithelioid granulomata were observed and the granulomata became disseminated widely during the experimental period. These findings in model mice suggest that gamma(delta) T cells, rather than restricting mycobacterial growth, may play a crucial role in development of epithelioid granulomata similar to those seen consistently in bovine paratuberculosis. The results of this study may have relevance to our understanding of the pathogenesis of paratuberculosis in ruminants, in which a prominent number of gamma(delta) T cells exist in the lymphoid system.  相似文献   

17.
The objective of this paper was to study the changes of some cytokines and neuroendocrine hormones in vaccinated and unvaccinated pigs that were naturally infected by a PRRSV-1 (porcine reproductive and respiratory syndrome virus) heterologous field strain. We analyzed gene expression of pro-inflammatory (TNF-α, IL-1β, MCP-1, IL-6), pro-immune (IFN-γ) and anti-inflammatory cytokines (IL-10) in PBMC, as well as hormonal (GH and cortisol) levels in blood samples of pigs obtained in a field trial previously reported [Martelli P, Gozio S, Ferrari L, Rosina S, De Angelis E, Quintavalla C, et al. Efficacy of a modified-live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine in pigs naturally exposed to a heterologous European (Italian cluster) field strain: clinical protection and cell-mediated immunity. Vaccine 2009;27:3788-99]. All vaccinated pigs showed an increase in pro-inflammatory and pro-immune cytokine gene expression with respect to controls and a prompt increase in GH that could be consistently associated with pro-inflammatory cytokines in sustaining innate immunity; moreover, the higher levels of cortisol indicates the activation of the hypothalamus-pituitary-adrenal (HPA) axis response. In contrast, unvaccinated pigs showed down-regulation of the cortisol and GH responses, and the pro-inflammatory and pro-immune cytokines remained at a basal or low level, with an increase of TNF-α and IL-6 in association with a higher level of IL-10 in the late phase of natural infection. The associated trends of pro-inflammatory and anti-inflammatory cytokines together with the cortisol level demonstrate that a previous vaccination promotes an early immune responsiveness in pigs and a more efficient control of inflammation in the late phase of infection with a heterologous PRRSV isolate; both events could sustain clinical protection.  相似文献   

18.
Pathogens that are transmitted between the environment, wildlife, livestock and humans represent major challenges for the protection of human and domestic animal health, the economic sustainability of agriculture, and the conservation of wildlife. Among such pathogens, the genus Mycobacterium is well represented by M. bovis, the etiological agent of bovine tuberculosis, M. avium ssp. paratuberculosis (Map) the etiological agent of Johne disease, M. avium ssp. avium (Maa) and in a few common cases by other emergent environmental mycobacteria. Epidemiologic surveys performed in Europe, North America and New Zealand have demonstrated the existence and importance of environmental and wildlife reservoirs of mycobacterial infections that limit the attempts of disease control programmes. The aim of this review is to examine the zoonotic aspects of mycobacteria transmitted from the environment and wildlife. This work is focused on the species of two main groups of mycobacteria classified as important pathogens for humans and animals: first, M. bovis, the causative agent of bovine tuberculosis, which belongs to the M. tuberculosis complex and has a broad host range including wildlife, captive wildlife, domestic livestock, non-human primates and humans; the second group examined, is the M. avium-intracellulare complex (MAC) which includes M. avium ssp. avium causing major health problems in AIDS patients and M. avium ssp. paratuberculosis the etiological agent of Johne disease in cattle and identified in patients with Crohn disease. MAC agents, in addition to a broad host range, are environmental mycobacteria found in numerous biotopes including the soil, water, aerosols, protozoa, deep litter and fresh tropical vegetation. This review examines the possible reservoirs of these pathogens in the environment and in wildlife, their role as sources of infection in humans and animals and their health impact on humans. The possibilities of control and management programmes for these mycobacterial infections are examined with regards to the importance of their natural reservoirs.  相似文献   

19.
In countries where cattle tuberculosis caused by Mycobacterium bovis (Mbov) and paratuberculosis caused by Mycobacterium avium subsp. paratuberculosis (Mptb) are present, testing strategies for the Mbov eradication have to discriminate between these two infections. Present indirect tests are based on the analysis of the specific cellular immune response (DTH, IFN-gamma) against crude mycobacterial antigens (avian and bovine PPD). In this study, we compared the evolution of the IFN-gamma responses of animals experimentally infected with Mbov, Mptb, or inoculated with Mycobacterium phlei. Mbov inoculation induced a strong IFN-gamma response that allows rapid classification of the status of the animals following interpretation criteria set up by us. Experimental inoculation with M. phlei induced sensitisation to mycobacterial antigens as detected by the IFN-gamma test but these reactions were of short duration, therefore, repeated testing allows us to define these animals as aspecific reactors. IFN-gamma response induced after oral inoculation of calves with Mptb was of low intensity and ratio of responses measured against avian versus bovine PPD did not allow a clear diagnostic at least for the six first month of infection.  相似文献   

20.
寄生虫在入侵机体时必须具备逃避机体免疫,破坏宿主免疫屏障才能感染,这种入侵过程必然和宿主机体的免疫系统发生联系,不但使宿主的先天免疫细胞功能缺失,而且获得性免疫也受到抑制。寄生虫感染均不同程度地伴随免疫损伤,宿主在感染寄生虫后产生的免疫应答中,细胞因子作为免疫过程中的介质起到关键作用,主要是调节机体细胞免疫抗虫,保护机体不被感染,其中巨噬细胞是主要功能的承担者。本文将阐述细胞因子在寄生虫感染过程中所发挥的免疫作用,为解决寄生虫感染的防控问题奠定基础,同时为寄生虫的研究提供新的思路。  相似文献   

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