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1.
Infect Immun ; 79(4): 1647-53, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21282414

RESUMEN

Cryptosporidiosis is an important diarrheal disease of humans and neonatal livestock caused by Cryptosporidium spp. that infect epithelial cells. Recovery from Cryptosporidium parvum infection in adult hosts involves CD4(+) T cells with a strong Th1 component, but mechanisms of immunity in neonates are not well characterized. In the present investigation with newborn mice, similar acute patterns of infection were obtained in C57BL/6 wild-type (WT) and T and B cell-deficient Rag2(-/-) mice. In comparison with uninfected controls, the proportion of intestinal CD4(+) or CD8(+) T cells did not increase in infected WT mice during recovery from infection. Furthermore, infection in neonatal WT mice depleted of CD4(+) T cells was not exacerbated. Ten weeks after WT and Rag2(-/-) mice had been infected as neonates, no patent infections could be detected. Treatment at this stage with the immunosuppressive drug dexamethasone produced patent infections in Rag2(-/-) mice but not WT mice. Expression of inflammatory markers, including gamma interferon (IFN-γ) and interleukin-12p40 (IL-12p40), was higher in neonatal WT mice than in Rag2(-/-) mice around the peak of infection, but IL-10 expression was also higher in WT mice. These results suggest that although CD4(+) T cells may be important for elimination of C. parvum, these cells are dispensable for controlling the early acute phase of infection in neonates.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Criptosporidiosis/inmunología , Criptosporidiosis/patología , Animales , Animales Recién Nacidos , Separación Celular , Cryptosporidium parvum/inmunología , Citocinas/biosíntesis , Citocinas/inmunología , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Citometría de Flujo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
2.
J Immunol ; 184(11): 6043-52, 2010 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-20427769

RESUMEN

Rapid cell-mediated immune responses, characterized by production of proinflammatory cytokines, such as IFN-gamma, can inhibit intraerythrocytic replication of malaria parasites and thereby prevent onset of clinical malaria. In this study, we have characterized the kinetics and cellular sources of the very early IFN-gamma response to Plasmodium falciparum-infected RBCs among human PBMCs. We find that NK cells dominate the early (12-18 h) IFN-gamma response, that NK cells and T cells contribute equally to the response at 24 h, and that T cells increasingly dominate the response from 48 h onward. We also find that although gammadelta T cells can produce IFN-gamma in response to P. falciparum-infected RBCs, they are greatly outnumbered by alphabeta T cells, and thus, the majority of the IFN-gamma(+) T cells are alphabeta T cells and not gammadelta T cells; gammadelta T cells are, however, an important source of TNF. We have previously shown that NK cell responses to P. falciparum-infected RBCs require cytokine and contact-dependent signals from myeloid accessory cells. In this study, we demonstrate that NK cell IFN-gamma responses to P. falciparum-infected RBCs are also crucially dependent on IL-2 secreted by CD4(+) T cells in an MHC class II-dependent manner, indicating that the innate response to infection actually relies upon complex interactions between NK cells, T cells, and accessory cells. We conclude that activation of NK cells may be a critical function of IL-2-secreting CD4(+) T cells and that standard protocols for evaluation of Ag-specific immune responses need to be adapted to include assessment of NK cell activation as well as T cell-derived IL-2.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Eritrocitos/parasitología , Células Asesinas Naturales/inmunología , Malaria Falciparum/inmunología , Receptor Cross-Talk/inmunología , Linfocitos T CD4-Positivos/metabolismo , Separación Celular , Citometría de Flujo , Humanos , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-2/biosíntesis , Interleucina-2/inmunología , Células Asesinas Naturales/metabolismo , Activación de Linfocitos/inmunología , Plasmodium falciparum/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
3.
J Infect Dis ; 200(10): 1548-55, 2009 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-19821721

RESUMEN

Type II interferon (IFN), IFN-gamma, is important in innate immunity to the intestinal protozoan parasite Cryptosporidium species, which infects epithelial cells (enterocytes). This investigation is, to our knowledge, the first to characterize the role of type I IFN in innate immunity to this parasite. Pretreatment of human or murine enterocyte cell lines with IFN-alpha/beta inhibited parasite development, and we identified that a key mechanism of cytokine action was to prevent parasite invasion of enterocytes. IFN-alpha/beta was rapidly expressed by infected murine enterocytes and also by bone marrow-derived dendritic cells that were exposed to live parasites. Treatment of neonatal severe combined immunodeficiency mice with anti-IFN-alpha/beta neutralizing antibodies before infection increased oocyst reproduction, as measured at the peak of infection, and parasite numbers in gut epithelium were also increased 2 days after infection. The latter observation correlated with strong intestinal expression of both IFN-alpha and IFN-beta messenger RNA within 24 h after infection. Treatment with anti-IFN-alpha/beta, however, did not reduce early expression of IFN-gamma. These findings identify a novel early innate host response against Cryptosporidium parvum involving IFN-alpha/beta.


Asunto(s)
Criptosporidiosis/inmunología , Cryptosporidium parvum/inmunología , Enterocitos/inmunología , Inmunidad Innata , Interferón-alfa/inmunología , Interferón beta/inmunología , Animales , Células CACO-2 , Enterocitos/parasitología , Humanos , Interferón-alfa/genética , Interferón beta/genética , Ratones , ARN Mensajero
4.
Infect Immun ; 77(11): 5044-9, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19687195

RESUMEN

A gamma interferon (IFN-gamma)-dependent innate immune response operates against the intestinal parasite Cryptosporidium parvum in T- and B-cell-deficient SCID mice. Although NK cells are a major source of IFN-gamma in innate immunity, their protective role against C. parvum has been unclear. The role of NK cells in innate immunity was investigated using Rag2-/- mice, which lack T and B cells, and Rag2-/- gammac-/- mice, which, in addition, lack NK cells. Adult mice of both knockout lines developed progressive chronic infections; however, on most days the level of oocyst excretion was higher in Rag2-/- gammac-/- mice and these animals developed morbidity and died, whereas within the same period the Rag2-/- mice appeared healthy. Neonatal mice of both mouse lines survived a rapid onset of infection that reached a higher intensity in Rag2-/- gammac-/- mice. Significantly, similar levels of intestinal IFN-gamma mRNA were expressed in Rag2-/- and Rag2-/- gammac-/- mice. Also, infections in each mouse line were exacerbated by treatment with anti-IFN-gamma neutralizing antibodies. These results support a protective role for NK cells and IFN-gamma in innate immunity against C. parvum. In addition, the study implies that an intestinal cell type other than NK cells may be an important source of IFN-gamma during infection and that NK cells may have an IFN-gamma-independent protective role.


Asunto(s)
Criptosporidiosis/inmunología , Inmunidad Innata , Interferón gamma/inmunología , Intestinos/inmunología , Células Asesinas Naturales/inmunología , Animales , Cryptosporidium parvum/inmunología , Ratones , Ratones Noqueados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
5.
Cell Microbiol ; 11(9): 1354-64, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19473199

RESUMEN

The apicomplexan parasite Cryptosporidium parvum, the agent of cryptosporidiosis, primarily infects and reproduces in enterocytes. Interferon (IFN)-gamma is important for early control of the infection and acts directly on enterocytes to inhibit parasite development, although complete inhibition is not obtained. Addressing this latter observation, an investigation was made of the modulatory effect of C. parvum infection on IFN-gamma-dependent enterocyte gene expression. Initial studies showed that IFN-gamma-induced expression of indoleamine 2, 3 dioxygenase (IDO) mRNA and protein in CMT-93 cells was abrogated by C. parvum infection. Infection also inhibited IDO expression by the human enterocyte cell lines HT29 and Caco-2. Expression of IFN-gamma-inducible genes important in the development of immune responses, including major histocompatibility complex class II and CIITA, was also inhibited by the parasite. Investigating a possible mechanism for these findings, it was shown that infection caused depletion of STAT1alpha protein, a key transcription factor in IFN-gamma signalling. These findings indicate C. parvum interferes with IFN-gamma-dependent gene expression in enterocytes and suggest this activity could be a novel immuno-evasive strategy employed by the parasite.


Asunto(s)
Cryptosporidium parvum/inmunología , Enterocitos/inmunología , Enterocitos/parasitología , Regulación de la Expresión Génica , Interferón gamma/inmunología , Transducción de Señal , Animales , Línea Celular , Perfilación de la Expresión Génica , Humanos , Factor 3 de Genes Estimulados por el Interferón/metabolismo , Ratones
6.
J Immunol ; 182(10): 6426-34, 2009 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-19414796

RESUMEN

IFN-gamma emanating from NK cells is an important component of innate defense against infection. In this study, we demonstrate that, following in vitro stimulation of human peripheral blood NK cells with a variety of microbial ligands, CD56(dim) as well as CD56(bright) NK cells contribute to the overall NK cell IFN-gamma response with, for most cell donors, IFN-gamma(+) CD56(dim) NK cells outnumbering IFN-gamma(+) CD56(bright) NK cells. We also observe that the magnitude of the human NK IFN-gamma response to microbial ligands varies between individuals; that the antimicrobial response of CD56(bright), but not CD56(dim), NK cells is highly correlated with that of myeloid accessory cells; and that the ratio of IFN-gamma(+) CD56(dim) to IFN-gamma(+) CD56(bright) NK cells following microbial stimulation differs between individuals but remains constant for a given donor over time. Furthermore, ratios of IFN-gamma(+) CD56(dim) to IFN-gamma(+) CD56(bright) NK cells for different microbial stimuli are highly correlated and the relative response of CD56(dim) and CD56(bright) NK cells is highly significantly associated with killer Ig-like receptor (KIR) genotype. These data reveal an influence of KIR genotype, possibly mediated via NK cell education, on the ability of NK cells to respond to nonviral infections and have implications for genetic regulation of susceptibility to infection in humans.


Asunto(s)
Antígenos Bacterianos/inmunología , Antígeno CD56/metabolismo , Interferón gamma/biosíntesis , Células Asesinas Naturales/inmunología , Subgrupos Linfocitarios/inmunología , Receptores KIR/inmunología , Antígeno CD56/inmunología , Citocinas/inmunología , Citometría de Flujo , Genotipo , Humanos , Interferón gamma/inmunología , Células Asesinas Naturales/metabolismo , Activación de Linfocitos/inmunología , Subgrupos Linfocitarios/metabolismo
7.
Microbes Infect ; 10(9): 995-1004, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18762264

RESUMEN

Tuberculosis is the most important bacterial infection world wide. The causative agent, Mycobacterium tuberculosis survives and proliferates within macrophages. Immune mediators such as interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha) activate macrophages and promote bacterial killing. IFN-gamma is predominantly secreted by innate cells (mainly natural killer (NK) cells) and by T cells upon instruction by interleukin 12 (IL-12) and IL-18. These cytokines are primarily produced by dendritic cells and macrophages in response to Toll-like receptor (TLR) signalling interaction with tubercle bacilli. These signals also induce pro-inflammatory cytokines (including IL-1beta and TNF-alpha), chemokines and defensins. The inflammatory environment further recruits innate effector cells such as macrophages, polymorphonuclear neutrophils (PMN) and NK cells to the infectious foci. This eventually leads to the downstream establishment of acquired T cell immunity which appears to be protective in more than 90% of infected individuals. Robust innate immune activation is considered an essential prerequisite for protective immunity and vaccine efficacy. However, data published so far provide a muddled view of the functional importance of innate immunity in tuberculosis. Here we critically discuss certain aspects of innate immunity, namely PMN, TLRs and NK cells, as characterised in tuberculosis to date, and their contribution to protection and pathology.


Asunto(s)
Inmunidad Innata , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Humanos , Células Asesinas Naturales/inmunología , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/fisiología , Neutrófilos/inmunología , Receptores Toll-Like/inmunología , Tuberculosis/fisiopatología
8.
PLoS Pathog ; 2(12): e118, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17154717

RESUMEN

Data from a variety of experimental models suggest that natural killer (NK) cells require signals from accessory cells in order to respond optimally to pathogens, but the precise identity of the cells able to provide such signals depends upon the nature of the infectious organism. Here we show that the ability of human NK cells to produce interferon-gamma in response to stimulation by Plasmodium falciparum-infected red blood cells (iRBCs) is strictly dependent upon multiple, contact-dependent and cytokine-mediated signals derived from both monocytes and myeloid dendritic cells (mDCs). Contrary to some previous reports, we find that both monocytes and mDCs express an activated phenotype following short-term incubation with iRBCs and secrete pro-inflammatory cytokines. The magnitude of the NK cell response (and of the KIR(-) CD56(bright) NK cell population in particular) is tightly correlated with resting levels of accessory cell maturation, indicating that heterogeneity of the NK response to malaria is a reflection of deep-rooted heterogeneity in the human innate immune system. Moreover, we show that NK cells are required to maintain the maturation status of resting mDCs and monocytes, providing additional evidence for reciprocal regulation of NK cells and accessory cells. However, NK cell-derived signals are not required for activation of accessory cells by either iRBCs or bacterial lipolysaccharide. Together, these data suggest that there may be differences in the sequence of events required for activation of NK cells by non-viral pathogens compared to the classical model of NK activation by virus-infected or major histocompatibility complex-deficient cells. These findings have far-reaching implications for the study of immunity to infection in human populations.


Asunto(s)
Comunicación Celular/fisiología , Interferón gamma/metabolismo , Células Asesinas Naturales/metabolismo , Malaria Falciparum/metabolismo , Células Mieloides/fisiología , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Comunicación Celular/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Eritrocitos/parasitología , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Interferones/fisiología , Interleucina-2/fisiología , Células Asesinas Naturales/inmunología , Lectinas Tipo C , Malaria Falciparum/inmunología , Células Mieloides/inmunología , Plasmodium falciparum/inmunología , Plasmodium falciparum/patogenicidad , Transducción de Señal/fisiología
9.
J Immunol ; 175(11): 7466-73, 2005 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-16301654

RESUMEN

Human NK cells can respond rapidly to Plasmodium falciparum-infected RBC (iRBC) to produce IFN-gamma. In this study, we have examined the heterogeneity of this response among malaria-naive blood donors. Cells from all donors become partially activated (up-regulating CD69, perforin, and granzyme) upon exposure to iRBC but cells from only a subset of donors become fully activated (additionally up-regulating CD25, IFN-gamma, and surface expression of lysosomal-associated membrane protein 1 (LAMP-1)). Although both CD56dim and CD56bright NK cell populations can express IFN-gamma in response to iRBC, CD25 and LAMP-1 are up-regulated only by CD56dim NK cells and CD69 is up-regulated to a greater extent in this subset; by contrast, perforin and granzyme A are preferentially up-regulated by CD56bright NK cells. NK cells expressing IFN-gamma in response to iRBC always coexpress CD69 and CD25 but rarely LAMP-1, suggesting that individual NK cells respond to iRBC either by IFN-gamma production or cytotoxicity. Furthermore, physical contact with iRBC can, in a proportion of donors, lead to NK cell cytoskeletal reorganization suggestive of functional interactions between the cells. These observations imply that individuals may vary in their ability to mount an innate immune response to malaria infection with obvious implications for disease resistance or susceptibility.


Asunto(s)
Eritrocitos/microbiología , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Plasmodium falciparum/inmunología , Animales , Antígenos CD/biosíntesis , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Antígenos de Diferenciación de Linfocitos T/inmunología , Donantes de Sangre , Antígenos CD5/biosíntesis , Antígenos CD5/inmunología , Comunicación Celular/inmunología , Células Cultivadas , Citometría de Flujo , Humanos , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Células Asesinas Naturales/microbiología , Lectinas Tipo C , Proteína 1 de la Membrana Asociada a los Lisosomas/biosíntesis , Proteína 1 de la Membrana Asociada a los Lisosomas/inmunología , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/inmunología , Microscopía Confocal , Perforina , Proteínas Citotóxicas Formadoras de Poros , Receptores de Interleucina-2/biosíntesis , Receptores de Interleucina-2/inmunología , Regulación hacia Arriba
10.
Int J Parasitol ; 34(13-14): 1517-28, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15582528

RESUMEN

Natural killer (NK) cells are lymphoid cells that mediate significant cytotoxic activity and produce high levels of pro-inflammatory cytokines in response to infection. During viral infection, NK cell cytotoxicity and cytokine production is induced principally by monocyte-macrophage- and dendritic cell-derived cytokines but virally encoded ligands for NK cells are also beginning to be described. NK derived interferon-gamma (IFN-gamma) production is also essential for control of several protozoal infections including toxoplasmosis, trypanosomiasis, leishmaniasis and malaria. The activation of NK cells by protozoan pathogens is also believed to be cytokine-mediated although some recent studies suggest that direct recognition of parasites by NK cells also occurs. Both indirect signalling via accessory cell-derived cytokines and direct signalling, presumably through NK receptors, are needed in order for human malaria parasites (Plasmodium falciparum) to optimally stimulate NK activity.


Asunto(s)
Células Asesinas Naturales/inmunología , Infecciones por Protozoos/inmunología , Humanos , Inmunidad Innata , Activación de Linfocitos , Malaria/inmunología , Receptores Inmunológicos/metabolismo
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