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PubMed1988

Biochemical host response to interferon-beta.

To assess influence of host response to interferon-beta (IFN-beta), on biochemical parameters, beta 2-microglobulin (beta 2-M) and neopterin were evaluated in 15 and 12 patients respectively before and 24 h after 1-46 X 10(6) IU intravenously (i.v.) IFN-beta given every other day. In 4 additional patients, both molecules were determined before and after 24, 48, 72, and 96 h of weekly IFN-beta injections. Serum beta2-M levels significantly increased 24 h after IFN-beta administration in the overall group of 15 patients treated with the alternate day schedule (p = 0.003) as well as in the group of patients treated with the weekly schedule (p = 0.00003). Maximum induction of beta 2-M was observed 24 h after a single weekly IFN-beta injection, but the levels of this protein 72 h after still remained significantly higher than baseline values (p = 0.001). This demonstrates the progressive accumulation of beta 2-M in the circulation produced by the continuous IFN administration. Nevertheless, in patients treated with both IFN treatment schedules, a clear correlation between the increments of beta 2-M and the IFN-beta doses was observed (p = 0.00002 and p = 0.0016 for the alternate day and the weekly schedule respectively). Furthermore the under curve area (AUC) of 48 h beta 2-M levels after IFN administration significantly rose (p less than 0.05) with increasing IFN doses in 4/6 patients. In spite of the accumulation of beta 2-M in the circulation, the overall serum values of this protein 24 h after each successive IFN-injection, in the 15 patients receiving the alternate-day treatment, were significantly higher than before the immediate preceding dose both in patients with initially normal and those with initially high base levels (p = 0.00055 and p = 0.011, respectively). As with beta 2-M, neopterin levels significantly rose during IFN treatment (p less than 0.05) in the group of patients as a whole. After single weekly IFN-beta injections, maximum induction of neopterin was observed 24 h after administration, then the levels of this molecule slowly declined towards the baseline levels, but 96 h after, its levels were still significantly elevated (p less than 0.00001). Neopterin induction was not related to IFN-beta doses, but the levels of this molecule both before and after IFN administration were correlated with an increase in the number of IFN injections (p = 0.0006 and p = 0.0009, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1996

Diurnal variations in the human host response to endotoxin.

To investigate diurnal variations in the host response to endotoxin, Salmonella abortus equi endotoxin (0.8 ng/kg) was given intravenously to healthy men in a placebo-controlled design at 0900 or 1900 h. The time course of rectal temperature and the plasma levels of tumor necrosis factor- alpha (TNF-alpha), interleukin-6 (IL-6), adrenocorticotropic hormone (ACTH), and cortisol were monitored for 11 h following the injections. The time of day did not affect the endotoxin-induced increase in plasma TNF-alpha or IL-6. However, subjects who received endotoxin in the evening, when endogenous glucocorticoid levels were low, showed about twice the increases in rectal temperature and plasma ACTH and cortisol levels as those who received endotoxin in the morning, when endogenous glucocorticoid levels were high. These results demonstrate diurnal variations in the human susceptibility to endotoxin that may be due to a suppression of the biologic effects of TNF-alpha and IL-6 by endogenous glucocorticoids.

Adrenocorticotropic Hormone↗

PubMed1996

Effects of granulocyte colony-stimulating factor on plasma cytokine and cytokine receptor levels and on the in vivo host response to endotoxin in healthy men.

We investigated the effects of granulocyte colony-stimulating factor (G-CSF) on cytokine and cytokine receptor plasma levels and on the in vivo host response to Salmonella abortus equi endotoxin in healthy males. Twenty volunteers received 0.8 ng/kg endotoxin and saline intravenously 1 week apart in randomized order. Twelve hours before both experiments, 10 of these subjects were pretreated with 300 micrograms G-CSF subcutaneously. G-CSF itself increased granulocyte and monocyte counts and the plasma levels of tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptors (sTNF-R) p55, and p75 and interleukin-1 receptor antagonist (IL-1ra). G-CSF did not influence plasma IL-1 beta and IL-6 levels. In the G-CSF-pretreated subjects endotoxin-induced surges in rectal temperature and in the plasma levels of TNF-alpha plasma levels were about 50% increased, and surges in the plasma levels of both sTNF-Rs and IL-1ra were about twice as high as in the control group. Endotoxin-induced increases in IL-6, cortisol, and heart rate were not modified by G-CSF pretreatment. Endotoxin administration induced a transient 50% reduction in leukocyte counts in the G-CSF-pretreated subjects that was not seen in the control group. We conclude that a single stand dose of G-CSF increases the plasma levels of cytokines and cytokine receptors and considerably modifies the host response of healthy humans to a low dose of endotoxin.

Bacterial Toxins↗

PubMed1995

Human host response to Mycobacterium tuberculosis.

Despite the importance of tuberculosis as the leading cause of death due to infectious disease in the world, it has only been recently that an understanding of the human host response in this infection has begun to emerge. The key components of this response are cytokines and components of cellular immunity, predominantly T-lymphocytes and macrophages. Though the relationships among the components of the immune response are complex, it seems likely that in response to mycobacterial infection associated with active disease, cytokines such as TNF-alpha and IL-1 beta are produced; these cytokines serve to recruit more lymphocytes, generally of the T(H) (T helper) phenotype, which then produces substances such as the macrophage activating factor interferon-gamma. Macrophages activated by IFN-gamma ar thus stimulating to enhance intracellular killing of mycobacteria. The role of other cytokines, such as IL-6 and IL-8, both of which are induced by M. tuberculosis or its cell was components, is less clear. Further elucidation of the human host response to tuberculosis should help in the development of new vaccines and treatment strategies.

Cytokines↗

PubMed2005

The host response of CD28-deficient mice to Pneumocystis infection.

Pneumocystis infection leads to a life threatening pneumonia in susceptible individuals. While depletion or dysfunction of CD4+T cells is a key determinant of susceptibility to Pneumocystis, the host response that leads to resolution of infection or lung injury is less well understood. We had previously shown that mice deficient in the T cell costimulatory molecule CD28 are susceptible to infection with Pneumocystis. A detailed analysis revealed that they clear Pneumocystis with delayed kinetics. This is associated with an influx of naïve CD8+ T cells. Depletion of CD8+ T cells did not alter organism burden, suggesting these cells are not responsible for clearance. Analysis of the cytokine milieu demonstrated a consistent increase in mRNA for IL-10 and IFN-gamma in the CD28-deficient mice. These data suggest that CD28 function in important in the efficiency of the host response to Pneumocystis pneumonia.

Animals↗

PubMed2001

CCSP modulates airway dysfunction and host responses in an Ova-challenged mouse model.

Clara cell secretory protein (CCSP) is synthesized by nonciliated bronchiolar cells in the lung and modulates lung inflammation to infection. To determine the role of CCSP in the host response to allergic airway disease, CCSP-deficient [(-/-)] mice were immunized twice with ovalbumin (Ova) and challenged by Ova (2 or 5 mg/m(3)) aerosol. After 2, 3, and 5 days of Ova aerosol challenge (6 h/day), airway reactivity was increased in CCSP(-/-) mice compared with wild-type [CCSP(+/+)] mice. Neutrophils were markedly increased in the bronchoalveolar lavage fluid of CCSP(-/-) Ova mice, coinciding with increased myeloperoxidase activity and macrophage inflammatory protein-2 levels. Lung histopathology and inflammation were increased in CCSP(-/-) compared with wild-type mice after Ova challenge. Mucus production, as assessed by histological staining, was increased in the airway epithelium of CCSP(-/-) Ova mice compared with that in CCSP(+/+) Ova mice. These data suggest a role for CCSP in airway reactivity and the host response to allergic airway inflammation and provide further evidence for the role of the airway epithelium in regulating airway responses in allergic disease.

Animals↗

PubMed2006

Gene expression profiling of the host response to HIV-1 B, C, or A/E infection in monocyte-derived dendritic cells.

Dendritic cells (DC) are among the first targets of human immunodeficiency virus type-1 (HIV-1) infection and in turn play a crucial role in viral transmission to T cells and in the regulation of the immune response. The major group of HIV-1 has diversified genetically based on variation in env sequences and comprise at least 11 subtypes. Because little is known about the host response elicited against different HIV-1 clade isolates in vivo, we sought to use gene expression profiling to identify genes regulated by HIV-1 subtypes B, C, and A/E upon de novo infection of primary immature monocyte-derived DC (iMDDCs). A total of 3700 immune-related genes were subjected to a significance analysis of microarrays (SAM); 656 genes were selected as significant and were further divided into 8 functional categories. Regardless of the time of infection, 20% of the genes affected by HIV-1 were involved in signal transduction, followed by 14% of the genes identified as transcription-related genes, and 7% were classified as playing a role in cell proliferation and cell cycle. Furthermore, 7% of the genes were immune response genes. By 72 h postinfection, genes upregulated by subtype B included the inhibitor of the matrix metalloproteinase TIMP2 and the heat shock protein 40 homolog (Hsp40) DNAJB1, whereas the IFN inducible gene STAT1, the MAPK1/ERK2 kinase regulator ST5, and the chemokine CXCL3 and SHC1 genes were induced by subtypes C and A/E. These analyses distinguish a temporally regulated host response to de novo HIV-1 infection in primary dendritic cells.

Cell Differentiation↗

PubMed2001

Role of tachykinins in the host response to murine gammaherpesvirus infection.

Tachykinins function not only as neurotransmitters but also as immunological mediators. We used infection of tachykinin-deficient (PPT-A(-/-)) mice and wild-type controls with murine gammaherpesvirus to assess the role of tachykinins in the host response to a virus infection. Although infection was ultimately controlled in PPT-A(-/-) mice, there were higher titers of infectious virus in the lungs, accompanied by a more rapid influx of inflammatory cells. Clearance of latently infected cells from the spleen was also delayed. This is the first report of the direct influence of tachykinins in the host response to a virus infection.

Animals↗

PubMed2005

Reduction of astrogliosis by early treatment of pneumococcal meningitis measured by simultaneous imaging, in vivo, of the pathogen and host response.

We developed a method for simultaneous in vivo biophotonic monitoring of pneumococcal meningitis and the accompanying neuronal injury in live transgenic mice. Streptococcus pneumoniae engineered for bioluminescence (lux) was used for direct visualization of disease progression and antibiotic treatment in a mouse model of meningitis. The host response was monitored in transgenic mice containing an inducible firefly luciferase (luc) reporter gene under transcriptional control of the mouse glial fibrillary acidic protein (GFAP) promoter. Based on the different spectra of light emission and substrate requirements for lux and luc, we were able to separately monitor the two reporters using a highly sensitive in vivo imaging system. The level of neuronal damage and recovery following antibiotic treatment was dependent on the time of treatment. This model has potential for simultaneous multiparameter monitoring and testing of therapies that target the pathogen or host response to prevent neuronal injury and recovery.

Animals↗

PubMed1997

Influence of the Ward colon tumor on the host response to endotoxin.

Cachexia and a decreased immune function are negative prognostic factors for cancer patients. While the decreased immunity results in a greater susceptibility to bacterial infection, the response of the host to the resulting infection is not clear. The experiments reported here were designed to evaluate the toxicity of endotoxin to rats with a transplantable Ward colon tumor (WCT) and to evaluate the mechanism of the observed increase in lethal toxicity. The lethal toxicity of endotoxin (lipopolysaccharide, LPS) at 5 mg/kg, i.p. was evaluated in the first of two experiments. Rats received LPS and were observed for morbidity and weight loss for a period of 11 days. A second experiment was done to evaluate the effect of LPS on the plasma nitrate/nitrite concentrations and plasma indicators of host tissue dysfunction. LPS was administered as previously described but blood and tissues were collected 5 h after LPS administration. LPS resulted in the death of 1 of 12 nontumor-bearing (NTB) rats and a transient weight loss in the survivors. This same dose of LPS, however, resulted in death for 10 of 12 WCT rats with tumor burdens less than 4% of body weight. The response of WCT rats 5 h after LPS was then compared with that of age-matched NTB rats. Plasma albumin concentrations were not affected by LPS in NTB rats but were significantly decreased in WCT rats. Peripheral blood gases were not consistently affected by LPS in either group. Peripheral blood white cell counts, except monocytes, were significantly decreased by LPS in both groups. Monocyte counts in peripheral blood were further reduced in WCT rats compared with NTB rats receiving LPS. The presence of the WCT significantly enhanced the LPS-associated increase in spleen weight. Liver weights were lower in LPS rats but there was no effect of the presence of WCT. The LPS-associated increase in plasma nitrate/nitrite concentration was enhanced by the WCT. The plasma arginine and citrulline concentrations were altered in a manner consistent with an increase in nitric oxide synthesis. An increase in plasma ornithine concentration suggests an increase in arginine metabolism by arginase. The plasma concentration of alanine aminotransferase was significantly elevated when WCT rats received LPS, suggesting enhanced hepatic dysfunction. The plasma blood urea nitrogen concentration was elevated by LPS to a greater extent in the WCT rats than in the NTB controls, indicating increased renal dysfunction. These results demonstrate that the Ward colon tumor increases the host lethal response to the endotoxin, a toxic product of bacterial infections. The mechanisms of lethality may include an increased nitric oxide synthesis in WCT rats and enhanced liver and renal toxicity.

Animals↗

PubMed2005

Contrasting effects of cyclooxygenase-1 (COX-1) and COX-2 deficiency on the host response to influenza A viral infection.

Influenza is a significant cause of morbidity and mortality worldwide despite extensive research and vaccine availability. The cyclooxygenase (COX) pathway is important in modulating immune responses and is also a major target of nonsteroidal anti-inflammatory drugs (NSAIDs) and the newer COX-2 inhibitors. The purpose of the present study was to examine the effect of deficiency of COX-1 or COX-2 on the host response to influenza. We used an influenza A viral infection model in wild type (WT), COX-1-/-, and COX-2-/- mice. Infection induced less severe illness in COX-2-/- mice in comparison to WT and COX-1-/- mice as evidenced by body weight and body temperature changes. Mortality was significantly reduced in COX-2-/- mice. COX-1-/- mice had enhanced inflammation and earlier appearance of proinflammatory cytokines in the BAL fluid, whereas the inflammatory and cytokine responses were blunted in COX-2-/- mice. However, lung viral titers were markedly elevated in COX-2-/- mice relative to WT and COX-1-/- mice on day 4 of infection. Levels of PGE2 were reduced in COX-1-/- airways whereas cysteinyl leukotrienes were elevated in COX-2-/- airways following infection. Thus, deficiency of COX-1 and COX-2 leads to contrasting effects in the host response to influenza infection, and these differences are associated with altered production of prostaglandins and leukotrienes following infection. COX-1 deficiency is detrimental whereas COX-2 deficiency is beneficial to the host during influenza viral infection.

Animals↗

PubMed2005

Cellular immune host response in acute cutaneous leishmaniasis.

OBJECTIVE: To evaluate cellular immune host response in various patterns of acute cutaneous leishmaniasis. DESIGN: It was a cross-sectional and comparative study. PLACE AND DURATION OF STUDY: The Armed Forces Institute of Pathology (AFIP) and Military Hospital (MH), Rawalpindi from 1996 to 1999. PATIENTS AND METHODS: Forty biopsies of active skin lesions after processing were studied for various immunophenotype cells by using monoclonal antibodies. Total as well as differential T cell counts were recorded in acute single, acute multiple and sporotrichoid lesions and in normal skin tissues. Non parametric Kruskal-Wallis Test for one way ANOVA was used to compare cell counts in these groups and p-value <0.05 was considered significant. RESULTS: No significant difference was seen in the histopathology, type of infiltrate and the ratio between the immune competent cells in acute single or multiple lesions. The results of analysis of total cell count, CD3+ cells and CD57+ (NK) cells were statistically different (p=<0.05 to p=<0.001) between acute forms of the disease and normal tissue but no difference was seen when acute forms were compared with each other. However, CD4+, CD8+ and CD19+(Plasma cells) counts difference was significant (p=<0.05 to p=<0.01), when sporotrichoid lesions were compared with other acute lesions (single and multiple). CONCLUSION: The sporotrichoid variant of cutaneous leishmaniasis may be due to a different parasite species, which provokes a different cellular immune response.

Acute Disease↗

PubMed2001

Host response to various treatments to reduce Salmonella infections in swine.

Host response was evaluated following the administration of various treatments, such as probiotics, prebiotics, and vaccination, to reduce Salmonella in swine. Response to the treatments were studied by the evaluation of phagocytosis rates by flow cytometry, by studying the activation of whole-blood phagocytes by bioluminescence, the production of IgA against S. Typhimurium, and by histopathology. Significant differences were observed in the activation of whole-blood phagocytes in all groups of treated pigs (P = 0.0001). In SC54 vaccinated pigs, a significant reduction of Salmonella in the ileum was observed (P < 0.05) and the production of IgA against S. Typhimurium was higher in this group in comparison to uninfected control pigs (P = 0.0007). Furthermore, significant histopathological (P < 0.05) changes were observed in SC54 vaccinated pigs. Villus height and mucus and goblet cells density in the small intestine were reduced in vaccinated pigs in comparison to infected control pigs. Taken together, these findings suggest that SC54 vaccine can stimulate local immunity and reduce the presence of Salmonella in the ileum in swine. Use of SC54 vaccine should thus be considered in further field experiments.

Animals↗

PubMed1997

Processing of mycobacterial lipids and effects on host responsiveness.

One of the most important opportunistic pathogens associated with AIDS is the Mycobacterium avium complex. M. avium infections are found in up to 70% of individuals in advanced stages of AIDS. The deficiency in our knowledge of these mycobacteria presents an obstacle to the development of a rational approach for controlling these life-threatening infections in immunocompromised persons. It is apparent that M. avium can replicate in host macrophages and persist for long periods. During this time, various components, particularly lipids, accumulate in host macrophages and contribute to the ability of this organism to upset the cytokine homeostasis necessary for controlling infections of this type. M. avium lipids are immunosuppressive and can induce a variety of cytokines and eicosanoids that affect general host responses. The intention of this review is to examine the postphagocytic processing of various M. avium lipids with respect to their ability to alter host responses, particularly in immunocompromised patients such as those infected with HIV.

AIDS-Related Opportunistic Infections↗

PubMed1990

Host responses in mediating sepsis and adult respiratory distress syndrome.

Despite significant advances in intensive care unit technology and mechanical ventilatory support, mortality due to adult respiratory distress syndrome (ARDS) or multiorgan failure (MOF) has not changed significantly within the past two decades. The key to improving survival requires understanding and modifying (or eliminating) factors that may initiate (or modulate) these syndromes. Infection, and the host responses to infection, are major etiological factors responsible for the induction and perpetuation of the injury to the lung and microvasculature in ARDS and MOF, and contribute to late mortality. While the pathogenesis of ARDS and MOF-complicating sepsis remains to be elucidated, bacterially derived (eg, endotoxin or lipopolysaccharides [LPS]) and host-derived humoral and cellular mediators are of importance in both disease states. In fact, the host response to infection (or injurious stimuli) may be a more critical determinant of the outcome of sepsis and ARDS than the original inciting stimulus. The pleiotropic effects of LPS are largely indirect, and are orchestrated via its ability to trigger the release of an array of host-derived mediators of inflammation. Several potential mechanisms of injury in ARDS, sepsis, and MOF have been suggested and include a variety of inflammatory cells (neutrophils, mononuclear phagocytes, platelets), activated complement and coagulation components, vasoactive mediators (kinins, arachidonic acid metabolites, lipids, peptides), reactive oxygen radicals, and diverse cytokines. Interactions between these humoral and cellular mediators appear to set in motion an amplified cascade of events culminating in cellular and tissue injury. In this article, several of these putative inflammatory mediators are discussed in detail, and the importance of cytokine networking and the possible role of nonimmune cells in the orchestration of the inflammatory response associated with ARDS and MOF are explained. Finally, future therapeutic strategies aimed at blocking or suppressing the release or effects of endogenous mediators may be the key to improving the outcome of these disorders.

Arachidonic Acid↗

PubMed2002

Enhancement of pentylenetetrazole-induced seizures by Shigella dysenteriae in LPS-resistant C3H/HeJ mice: role of the host response.

Convulsions and encephalopathy are common complications of Shiga toxin (Stx)-producing Shigella and enterohemorrhagic Escherichia coli infections. In previous studies, we demonstrated that Stx and lipopolysaccharide (LPS) act in concert to enhance mice sensitivity to pentylenetetrazole (PTZ)-induced seizures via mechanisms involving tumor necrosis factor alpha (TNFalpha), interleukinl beta and nitric oxide. To further elucidate the role of the host response in Shigella-related seizures, we studied the ability of Shigella dysenteriae and its products to modulate seizures in C3H/HeJ (lps(d/d)) and in C3H/HeN (lps(n/n) mice. Injection of S. dysenteriae 60R sonicate elevated plasma TNFalpha and enhanced the convulsive response to PTZ in both mouse strains. Induced TNFalpha levels were markedly lower in LPS-hyporesponsive C3H/HeJ mice than in LPS- responsive C3H/HeN mice: 7.4 ng/ml vs 44 ng/ml (induced by 4LD50). Accordingly, a higher dose of S. dysenteriae sonicate was needed to sensitize the C3H/HeJ mice to seizures. Stx or LPS alone did not enhance seizures in either strain. Stx together with LPS enhanced seizures in LPS-responsive mice, but not in LPS-hyporesponsive mice in which they induced only a minor elevation in TNFalpha levels (1.5 ng/ml). As compared to LPS-responsive mice, the LPS-hyporesponsive mice were less susceptible to the lethal effects of Shigella sonicate and were resistant to the lethal effect of purified Stx with LPS. These results demonstrate the crucial role of the host response with regard to the sensitivity to to LPS, and specifically TNFalpha production, in Shigella lethality and Shigella-related seizures.

Animals↗

PubMed2005

Escherichia coli, fimbriae, bacterial persistence and host response induction in the human urinary tract.

Urinary tract infections (UTI) are among the most common bacterial infections in humans. Symptomatic UTIs may be acute, recurrent or chronic but the most frequent form of UTI is asymptomatic bacteruria (ABU). In ABU, the mucosa remains inert, despite the presence of large bacterial numbers in urine. The difference in disease severity reflects the virulence of the infecting strain and the propensity of the host to respond to infection. It is essential to understand the molecular basis of disease diversity and the molecular interactions between bacteria and host that determine asymptomatic carriage and the transition to disease. We discuss the initial interactions between bacteria and the mucosal surfaces in the human urinary tract, and the bacterial factors involved in the breach of mucosal inertia. Specifically, the contribution of P and type 1 fimbriae to bacterial establishment and host response induction are investigated. The results show that P fimbriae serve as independent virulence factors when expressed by an ABU strain, by promoting the establishment of bacteriuria and the innate host response, which is the cause of symptoms and tissue damage. P fimbriae thus fulfil the molecular Koch postulates as independent virulence factors in the human urinary tract. Type 1 fimbriae, in contrast, did not act as virulence factors in this model, and thus appear to serve a different function in man than in the murine model.

Adhesins, Bacterial↗

PubMed2004

A human in vitro model system for investigating genome-wide host responses to SARS coronavirus infection.

BACKGROUND: The molecular basis of severe acute respiratory syndrome (SARS) coronavirus (CoV) induced pathology is still largely unclear. Many SARS patients suffer respiratory distress brought on by interstitial infiltration and frequently show peripheral blood lymphopenia and occasional leucopenia. One possible cause of this could be interstitial inflammation, following a localized host response. In this study, we therefore examine the immune response of SARS-CoV in human peripheral blood mononuclear cells (PBMCs) over the first 24 hours. METHODS: PBMCs from normal healthy donors were inoculated in vitro with SARS-CoV and the viral replication kinetics was studied by real-time quantitative assays. SARS-CoV specific gene expression changes were examined by high-density oligonucleotide array analysis. RESULTS: We observed that SARS-CoV was capable of infecting and replicating in PBMCs and the kinetics of viral replication was variable among the donors. SARS-CoV antibody binding assays indicated that SARS specific antibodies inhibited SARS-CoV viral replication. Array data showed monocyte-macrophage cell activation, coagulation pathway upregulation and cytokine production together with lung trafficking chemokines such as IL8 and IL17, possibly activated through the TLR9 signaling pathway; that mimicked clinical features of the disease. CONCLUSIONS: The identification of human blood mononuclear cells as a direct target of SARS-CoV in the model system described here provides a new insight into disease pathology and a tool for investigating the host response and mechanisms of pathogenesis.

Animals↗