A dichotomous role for nitric oxide in protection against blood stage malaria infection

Nitric oxide (NO) is cytotoxic and cytostatic to blood stage malaria parasites in vitro, but the precise mechanism(s) by which it mediates an effect in vivo is not known. In particular, whether or not control of acute parasitemia depends on the presence of NO is unclear. We have shown previously that blocking NO synthesis at the time of its induction may cause an increase in peak primary parasitemia during infection of mice with Plasmodium chabaudi, suggesting that NO may be parasiticidal in vivo. However, as recent data indicate that NO suppresses Th1 cell proliferation in vitro by downregulating IL-2 production, we have investigated whether this immunoregulatory function of NO affects its capacity for anti-malarial activity. Treatment of P. chabaudi-infected mice with the iNOS inhibitor aminoguanidine hemisulfate (AG) starting just prior to the peak of primary parasitemia caused a significant elevation and extension of the acute infection and led to a partial but significant abrogation of the suppression of spleen cell proliferation to both mitogen and specific antigen observed when NO synthesis was not blocked. In the absence of NO, levels of IL-2, but not of IFN-gamma, TNF-alpha, or of any Th2-regulated cytokines examined, increased significantly. However, when AG treatment was brought forward to the early ascending phase of primary parasitemia, significantly increased levels of IFN-gamma and TNF-alpha, as well as of IL-2, were observed over those for infected control mice similarly treated with phosphate-buffered saline. Moreover, despite the absence of NO, parasitemias of AG-treated mice were not significantly elevated. The effect of AG therefore appeared to be dependent upon the timing of its administration in vivo. We propose that during malaria infections, there is a dynamic balance between the regulatory and anti-parasitic roles of NO. While the immunosuppressive function of NO leads to a downregulation in vivo of production of IL-2, and indirectly of IFN-gamma and TNF-alpha, this perceived weakening of the host cell-mediated immune response is in part masked by the protective anti-malarial effects of NO itself.     

Protective role of interleukin-6 during Yersinia enterocolitica infection is mediated through the modulation of inflammatory cytokines

Yersinia enterocolitica is a gram-negative enteric pathogen responsible for a number of gastrointestinal disorders. A striking feature of the pathology of a Y. enterocolitica infection is inflammation. Recently, we demonstrated a role for interleukin-1alpha (IL-1alpha) in the establishment of intestinal inflammation in response to a Y. enterocolitica infection. A cytokine directly affected by IL-1 levels is IL-6. A previous report suggested that IL-6 plays an anti-inflammatory role during Y. enterocolitica infection, and in other systems IL-6 has been shown to be proinflammatory. Therefore, a closer examination of the roles of IL-6 and inflammatory cytokines in the control of Y. enterocolitica infection in IL-6(-/-) mice was undertaken. Y. enterocolitica organisms were more virulent in the IL-6(-/-) mice (60-fold decreased 50% lethal dose) and colonized systemic tissues more rapidly and to a higher level than in the wild-type mice. One role of IL-6 during a Y. enterocolitica infection may be the downmodulation of the inflammatory response. The IL-6(-/-) mice have a more robust T(H)1 T-cell response, as well as hyperinflammatory pathologies. These phenotypes appear to be due to the misregulation of tumor necrosis factor alpha, monocyte chemotactic protein 1, IL-10, transforming growth factor beta1, and gamma interferon in the IL-6(-/-) mouse. These data provide further insight into the intricate cytokine signaling pathways involved in the regulation of inflammatory responses and the control of bacterial infections.     

疫苗突破性感染概述

疫苗接种能够有效降低可预防疾病的发生率,但疫苗不能提供百分之百的保护率,接种疫苗后仍罹患疫苗所预防的疾病,称之为疫苗突破性感染。新型冠状病毒肺炎疫情仍在世界范围内持续流行,接种新冠疫苗后仍然感染新冠病毒的病例多有报道,正确认识疫苗突破性感染具有重要意义。本文旨在对突破性感染的定义、发生机理以及现状做综述,以期获得对疫苗...     

The pivotal role of carbonic anhydrase in malaria infection

Carbon dioxide (CO₂) is essential for the growth of intraerythrocytic malaria parasites to synthesize pyrimidine through CO₂ fixation and to regulate intracellular pH. CO₂ transport across the plasma membrane of erythrocytes is facilitated by carbonic anhydrase (CA). With the use of electron microscopy and CA-specific Hansson's stain, CA is found also in all the intraerythrocytic stages of Plasmodium falciparum. When CA inhibitors, including acetazolamide, potassium iodide, and sodium deoxycholate, were added to continuous culture of P. falciparum, they, particularly sodium deoxycholate, produced a marked reduction in parasitemia. These results explain the biochemical basis of some of the clinical conditions associated with malaria and strongly suggest that CA inhibitors have potential as a new class of antimalarials.     

The role of cytokines in the immune response to influenza A virus infection

Influenza A virus is one of the most important causes of respiratory tract diseases. It replicates in epithelial cells and leukocytes resulting in the production of immune mediators--cytokines, substances with various biological effects. Cytokines, as a part of innate immunity, favor the development of antiviral and TH 1-type immune responses. Cytokines also affect the adaptive immune response and disease manifestation. In the organism, the virus infection results in the production of chemotactic [a regulated upon activation, normal T cell-expressed and -secreted cytokine (RANTES), monocyte chemoattractant proteins (MCP) MCP-1, MCP-3, macrophage inflammatory protein 1 alpha (MIP- 1 alpha), interferon gamma-induced protein 10 (IP-10), and interleukin 8 (IL-8)], pro-inflammatory [IL- 1beta, IL-6, IL-18, and tumor necrosis factor alpha(TNF-alpha)] and antiviral [interferon (IFN) alpha/beta] cytokines. Whilst knowledge of the mechanisms underlying host and tissue specificity has advanced significantly, we still know relatively little about the function of cytokines released from different cells following influenza infection. In this review we deal with the role and mode of possible impact of cytokines on the disease pathogenesis and host immune response.     

Modulation of experimental blood stage malaria through blockade of the B7/CD28 T-cell costimulatory pathway

Recent studies have implicated cytokines associated with CD4+ T lymphocytes of both T helper (Th)1 and Th2 subsets in resistance to experimental blood stage malaria. As the B7/CD28 costimulatory pathway has been shown to influence the differentiation of Th cell subsets, we investigated the contribution of the B7 molecules CD80 and CD86 to Th1/Th2 cytokine and immunoglobulin isotype profiles and to the development of a protective immune response to malaria in NIH mice infected with Plasmodium chabaudi. Effective blockade of CD86/CD28 interaction was demonstrated by elimination of interleukin (IL)-4 and up-regulation of interferon (IFN)-gamma responses by P. chabaudi-specific T cells and by reduction of P. chabaudi-specific immunoglobulin G1 (IgG1). The shift towards a Th1 cytokine pattern corresponded with efficient control of acute parasitaemia but an inability to resolve chronic infection. Moreover, combined CD80/CD86 blockade by using anti-CD80 and anti-CD86 monoclonal antibodies raised IFN-gamma production over that seen with CD86 blockade alone, with augmentation of this Th1-associated cytokine reducing levels of peak primary parasitaemia. These results demonstrate that IL-4 production by T cells in P. chabaudi-infected NIH mice is dependent upon CD86/CD28 interaction and that IL-4 and IFN-gamma contribute significantly, at different times of infection, to host resistance to blood stage malaria. In addition, combined CD80/CD86 blockade resulted in preferential expansion of IFN-gamma-producing T cells during P. chabaudi infection, suggesting that costimulatory pathways other than B7/CD28 may contribute to T-cell activation during continuous antigen stimulation. This study indicates a role for B7/CD28 costimulation in modulating the CD4+ T-cell response during malaria, and further suggests involvement of this pathway in other infectious and autoimmune diseases in which the Th cell immune response is also skewed.     

Anti-parasite effects of cytokines in malaria

Cytokines induced during natural malaria infections, e.g., at crisis of a blood infection of Plasmodium cynomolgi, and during clinical paroxysms in human Plasmodium vivax infections, mediate killing of intra-erythrocytic blood stage malaria parasites. These cytokines, TNF and IFN-gamma, require additional, yet unidentified complementary factors that are present in "crisis" and "paroxysm" serum to kill intra-erythrocytic blood stage parasites. In contrast, cytokines, (mainly IFN-gamma) are able to effect killing of intra-hepatic stages of the parasite by themselves independent of serum complementary factors, suggesting that the mechanisms of killing may be different with respect to the two parasite stages. Cytokines also appear to be critical intermediates in mechanisms of clinical disease in malaria. Serum cytokine (TNF) levels and killing effects on blood stage malaria parasites were lower in patients who were exposed to endemic P. vivax malaria who had partial clinical immunity, than in non-immune patients. Evidence suggest that individuals acquire natural immunity to the disease by avoiding the induction of high levels of cytokines and complementary factors.     

Cellular mechanisms in immunity to blood stage infection

We studied mechanisms of immunity to blood stage infection in the mouse malarias Plasmodium vinckei and Plasmodium yoelii 17X. Infection with P. vinckei was uniformly lethal, whereas P. yoelii 17X caused a self-limited, nonlethal infection. Transfer of immune CD4+ T cells conferred protection against P. yoelii in nude mice. Previous studies by others had suggested that immunity to P. yoelii may be related to MHC class I expression on reticulocytes and found that CD8+ T cells alone transferred protection in immunodeficient mice. However, in our experiments, immune CD8+ T cells failed to transfer protection. In the P. vinckei system, both B cell-deficient and immunologically intact mice developed immunity to P. vinckei after parasite infection and drug cure. In vivo depletion of CD4+ T cells abrogated immunity in these immune mice. Adoptive transfer of CD4+ T cells failed to protect nude or normal mice from P. vinckei infection, but the transfer of immune CD4+ T cells reconstituted immunity in CD4-depleted immune mice. Splenectomy of immune mice resulted in the complete loss of immunity. Despite the fact that immunity to P. vinckei could be achieved with live parasite infection and drug cure, immunization of mice with killed P. vinckei with various adjuvants failed to protect mice from live challenge. In contrast, immunization with killed P. vinckei antigens in combination with attenuated Salmonella typhimurium SL3235 induced a high degree of protective immunity. These results suggest that induction of immunity against virulent malarias requires both induction of CD4+ T cells and certain splenic alterations caused by parasite infection or S. typhimurium.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inflammation,immunological reaction and role of infection in pulmonary hypertension

Inflammation underlies a wide variety of physiological and pathological processes. Acute inflammation is the initial response of the body to harmful stimuli. Chronic inflammation, by contrast, is a prolonged, dysregulated and maladaptive response that involves active inflammation, tissue destruction and attempts at tissue repair. Over the past few years, such persistent inflammation has been shown to be associated with pulmonary hypertension (PH). Substantial advances in basic and experimental science have illuminated the role of inflammation and the underlying cellular and molecular mechanisms that contribute to PH. This review summarizes the experimental and clinical evidence for inflammation in various types of PH. In addition, it assesses the current state of knowledge regarding the inducers/triggers of chronic inflammation and infection, as well as the inflammatory mediators and cells that are involved in PH. Infiltration of inflammatory cells, such as dendritic cells, macrophages, mast cells, T-lymphocytes and B-lymphocytes, in the vascular lesions and an elevation of serum/tissue concentrations of proinflammatory cytokines and chemokines and their contribution to pulmonary vascular remodelling are reported in detail. We review the data supporting the use of inflammatory markers as prognostic and predictive factors in PH. Finally, we consider how new insights into inflammation in PH may identify innovative therapeutic strategies.     

A bird's eye view on the role of dendritic cells in SARS-CoV-2 infection: Perspectives for immune-based vaccines

Coronavirus disease-19 (COVID-19) is a complex disorder caused by the pandemic diffusion of a novel coronavirus named SARS-CoV-2. Clinical manifestations vary from silent infection to severe pneumonia, disseminated thrombosis, multi-organ failure, and death. COVID-19 pathogenesis is still not fully elucidated, while increasing evidence suggests that disease phenotypes are strongly related to the virus-induced immune system's dysregulation. Indeed, when the virus-host cross talk is out of control, the occurrence of an aberrant systemic inflammatory reaction, named “cytokine storm,” leads to a detrimental impairment of the adaptive immune response. Dendritic cells (DCs) are the most potent antigen-presenting cells able to support innate immune and promote adaptive responses. Besides, DCs play a key role in the anti-viral defense. The aim of this review is to focus on DC involvement in SARS-CoV-2 infection to better understand pathogenesis and clinical behavior of COVID-19 and explore potential implications for immune-based therapy strategies.     

The immunological challenge to developing a vaccine to the blood stages of malaria parasites

Summary: Twenty‐one years after malaria antigens were first cloned, a vaccine still appears to be a long way off. There have been periods of great excitement, and in model systems, subunit vaccine homologs can induce robust protection. However, significant challenges exist concerning antigenic variation and polymorphism, immunological non‐responsiveness to individual vaccine antigens, parasite‐induced apoptosis of immune effector and memory cells, and immune deviation as a result of maternal immunity and alterations of dendritic cell function. Novel approaches will be required. This review addresses some of the approaches that might present malaria antigens in a way designed to induce superior immune responses or that target novel conserved epitopes. Cell‐mediated immunity, acting independently of antibody, may exert potent anti‐parasite effects, and identification of multiple target antigens/epitopes could lead to the development of vaccines with profound efficacy.     

A double-edged sword: The role of NKT cells in malaria and HIV infection and immunity

NKT cells are known to play a role against certain microbial infections, including malaria and HIV, two major global infectious diseases. NKT cells exhibit either protective or pathogenic role against malaria. They are depleted by HIV infection and have a direct pathogenic role against many opportunistic infections common in end-stage AIDS. This review discusses the various features of the interaction between NKT cells and malaria parasites and HIV, and the potential to harness this interaction for therapeutic and vaccine strategies.     

A role for TASK2 channels in the human immunological synapse

The immunological synapse is a transient junction that occurs when the plasma membrane of a T cell comes in close contact with an APC after recognizing a peptide from the antigen-MHC. The interaction starts when CRAC channels embedded in the T cell membrane open, flowing calcium ions into the cell. To counterbalance the ion influx and subsequent depolarization, K_v1.3 and KCa3.1 channels are recruited to the immunological synapse, increasing the extracellular K⁺ concentration. These processes are crucial as they initiate gene expression that drives T cell activation and proliferation. The T cell-specific function of the K_2P channel family member TASK2 channels and their role in autoimmune processes remains unclear. Using mass spectrometry analysis together with epifluorescence and super-resolution single-molecule localization microscopy, we identified TASK2 channels as novel players recruited to the immunological synapse upon stimulation. TASK2 localizes at the immunological synapse, upon stimulation with CD3 antibodies, likely interacting with these molecules. Our findings suggest that, together with K_v1.3 and KCa3.1 channels, TASK2 channels contribute to the proper functioning of the immunological synapse, and represent an interesting treatment target for T cell-mediated autoimmune disorders.     

Transmission of filarial infection through blood transfusion

Microfilariae can be transmitted by blood transfusion and they may be circulated in the recipient's blood but they do not develop into adult worms. Mortality associated with transfusion associated filarial infection is not documented but it may give rise to morbidity in transfusion recipients in terms of allergic reaction. The present study was carried out to investigate the association of post transfusion reactions and filarial infections in an endemic area. About 11,752 transfusion recipients were followed up and in 15 months period, 47 (0.4%) post transfusion reactions (PTR) were reported. Routine investigations for post transfusion reaction were carried out in all 47 patients and their respective blood donor. Moreover, blood culture, microfilaria detection by concentration technique, filarial antibody and antigen detection (both by ELISA) were done in all subjects. Out of 47 patients showing post transfusion reaction, 29 (61.7%) patients developed allergic reaction. Eighteen (38.3%) patients having allergic reaction did not have previous history of blood transfusion and 14 (29.8%) of them received transfusion from blood donors who was either positive for microfilaria, filarial antigen or antibody. Microfilaremia was demonstrated in 4 (8.5%) patients and 5 (10.6%) blood donors. Microfilaria was concurrently present in 2 patients and their respective donors. Filarial antibody was detected in 27 (56.5%) patients and 26 (55.3%) blood donors but microfilaria was detected in 3 (6.4%) and 4 (8.5%) subjects, respectively. Antigen detection test correlated with microfileraemic state of subjects. The result shows that transfusion associated filarial infection may be a probable cause for transfusion-associated morbidity in endemic areas. In 14 (29.8%) patients having allergic reactions, the probable cause was transfusion-associated filarial infection. Filarial antigen detection test was found to be more useful in detecting infections. Blood donors with active history of filarial infection should be deferred from donating blood. Filarial antigen detection test may be employed as screening test for blood donors, if possible.     

A role for N-methyl-D-aspartate receptors in norepinephrine-induced long-lasting potentiation in the dentate gyrus

Summary Mechanisms of action of norepinephrine (NE) on dentate gyrus granule cells were studied in rat hippocampal slices using extra- and intracellular recordings and measurements of stimulus and amino acid-induced changes in extracellular Ca²⁺ and K⁺ concentration. Bath application of NE (10–50 M) induced long-lasting potentiation of perforant path evoked potentials, and markedly enhanced high-frequency stimulus-induced Ca²⁺ influx and K⁺ efflux, actions blocked by -receptor antagonists and mimicked by agonists. Enhanced Ca²⁺ influx was primarily postsynaptic, since presynaptic [Ca²⁺]₀ in the stratum moleculare synaptic field was not altered by NE. Interestingly, the potentiation of both ionic fluxes and evoked population potentials were antagonized by the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (APV). Furthermore, NE selectively enhanced the [Ca²⁺]₀, [K⁺]₀ and extracellular slow negative field potentials elicited by iontophoretically applied NMDA, but not those induced by the excitatory amino acid quisqualate. These results suggest that granule cell influx of Ca²⁺ through NMDA ionophores is enhanced by NE via -receptor activation. In intracellular recordings, NE depolarized granule cells (4.8±1.1 mV), and increased input resistance (R_N) by 34±6.5%. These actions were also blocked by either the -antagonist propranolol or specific ₁-blocker metoprolol. Moreover, the depolarization and R_N increase persisted for long periods (93±12 min) after NE washout. In contrast, while NE, in the presence of APV, still depolarized granule cells and increased R_N, APV made these actions quickly reversible upon NE washout (16±9 min). This suggested that NE induction of long-term, but not short-term, plasticity in the dentate gyrus requires NMDA receptor activation. NE may be enhancing granule cell firing by some combination of blockade on the late Ca²⁺-activated K⁺ conductance and depolarization of granule cells, both actions that can bring granule cells into a voltage range where NMDA receptors are more easily activated. Furthermore, NE also elicited activity-independent long-lasting depolarization and R_N increases, which required functional NMDA receptors to persist.