Efficacy of therapeutic and prophylactic actions of ultralow doses of antibodies to gamma-interferon in experimental murine model of herpes virus]

The process of the disease due to herpes simplex virus types 1 and 2 (HSV-1 and 2) was studied on white uninbred mice weighing 10 to 12 g. The animals were infected intracerebrally or intraperitoneally. Intraperitoneal contamination of the animals with MS strain of HSV-2 was used for the experimental model of the herpes simplex infection. The prophylactic antiherpes action of ultralow doses of the human gamma-interferon antibodies (ULD of anti-IFN-gamma) at a course of its intragastral administration was evaluated. The preparation was shown to have a significant (p < 0.05) protective effect in a dose of 10 LD50, evident from a 10-fold decrease of the HSV-2 accumulation in the brain, a lower percentage of the animal deaths and an increase of the average lifespan of the animals by 3.3 days. The study of the therapeutic action of ULD of anti-IFN-gamma at a course of its intragastral administration showed that the preparation had no significant positive effect on the disease process in the animals infected with HSV-2 in a dose of 10 LD50. However, a positive effect associated with delayed virus replication in the brain was observed in the study on the therapeutic effect of ULD of anti-IFN-gamma after its intragastral administration to the mice infected with a sublethal dose of the virus.     

The in vivo antiviral activity of interleukin-12 is mediated by gamma interferon.

The injection of 20 ng of mouse interleukin-12 (IL-12) protects mice from a lethal infection with encephalomyocarditis virus. In vitro, an anti-gamma interferon (anti-IFN-gamma) monoclonal antibody but not an anti-IL-12 monoclonal antibody neutralizes the antiviral activity present in the supernatants of splenocytes stimulated with IL-12. Finally, IL-12 fails to protect 129 Sv/Ev IFN-gamma R0/0 mice against encephalomyocarditis virus infection. These results demonstrate that IL-12 exerts its antiviral activity through the induction of endogenous IFN-gamma.     

Experimental study of the prophylactic anti-influenza and interferon-inducing activity of epsilon-aminocaproic acid

Epsilon-aminocaproic acid, an original antifibrinolytic had a rapid and prolonged protective effect, thus lowering the death rate of experimental mice contaminated with virulent strains of the influenza virus. The protective effect of the acid was observed after its intraperitoneal administration in a dose of 20 mg/mouse 24 hours before contamination by the strain with the H3N2 antigenic formula and after intranasal application of 15 mg of epsilon-aminocaproic acid divided into 2 doses 2 days before contamination by the strain with the H1N1 antigenic formula. In the animals contaminated by the H1N1 influenza virus 5 days after subcutaneous administration of the drug in a dose of 30 mg there was detected in the lungs a much lower number of the infectious viruses 3 days after the contamination. It was shown that 3 and 6 weeks after initiation of the 5-day treatment course with subcutaneous administration of epsilon-aminocaproic acid in a daily dose of 90 mg/mouse the animal resistance to the H1N1 influenza virus increased. No interferonogenic activity after administration of epsilon-aminocaproic acid was observed in the mice.     

Influenza virus protecting RNA: an effective prophylactic and therapeutic antiviral

Another influenza pandemic is inevitable, and new measures to combat this and seasonal influenza are urgently needed. Here we describe a new concept in antivirals based on a defined, naturally occurring defective influenza virus RNA that has the potential to protect against any influenza A virus in any animal host. This “protecting RNA” (244 RNA) is incorporated into virions which, although noninfectious, deliver the RNA to those cells of the respiratory tract that are naturally targeted by infectious influenza virus. A 120-ng intranasal dose of this 244 protecting virus completely protected mice against a simultaneous challenge of 10 50% lethal doses with influenza A/WSN (H1N1) virus. The 244 virus also protected mice against strong challenge doses of all other subtypes tested (i.e., H2N2, H3N2, and H3N8). This prophylactic activity was maintained in the animal for at least 1 week prior to challenge. The 244 virus was 10- to 100-fold more active than previously characterized defective influenza A viruses, and the protecting activity was confirmed to reside in the 244 RNA molecule by recovering a protecting virus entirely from cloned cDNA. There was a clear therapeutic benefit when the 244 virus was administered 24 to 48 h after a lethal challenge, an effect which has not been previously observed with any defective virus. Protecting virus reduced, but did not abolish, replication of challenge virus in mouse lungs during both prophylactic and therapeutic treatments. Protecting virus is a novel antiviral, having the potential to combat human influenza virus infections, particularly when the infecting strain is not known or is resistant to antiviral drugs.     

Prevention of lethal respiratory vaccinia infections in mice with interferon-alpha and interferon-gamma

The antiviral efficacy of interferons (IFNs) was evaluated using a vaccinia intranasal infection model in mice in this study. We provide evidence that intranasal administration of IFN-alpha and IFN-gamma (days -1 to +3) resulted in 100 and 90% survival against a lethal respiratory vaccinia infection (8 LD50) in mice, respectively; whereas no animals in the placebo group survived through the study period (21 days). The IFN treatment consisted of a single daily dose of 5x10(3) U per mouse for 5 consecutive days. The efficacy of IFN-gamma was evident even when the IFN-gamma treatments started 1-2 days after infection and when a lower dose (2x10(3) U per mouse) was used. The treatment of IFN-alpha and IFN-gamma reduced the virus titers in the lungs of infected mice by 1000-10,000-fold, when the administration started 1 day after infection. Our data suggest that IFN-alpha and IFN-gamma are effective in protecting vaccinia-infected mice from viral replication in lungs and mortality, and may be beneficial in other human orthopoxvirus infections.     

Gamma interferon is not required for mucosal cytotoxic T-lymphocyte responses or heterosubtypic immunity to influenza A virus infection in mice

Heterosubtypic immunity (HSI) is defined as cross-protection against influenza virus of a different serotype than the virus initially encountered and is thought to be mediated by influenza virus-specific cytotoxic T lymphocytes (CTL). Since gamma interferon (IFN-gamma) stimulates cytotoxic cells, including antigen-specific CTL which may control virus replication by secretion of antiviral cytokines such as tumor necrosis factor alpha and IFN-gamma, we have investigated the mechanism of HSI by analyzing the role of IFN-gamma for HSI in IFN-gamma gene-deleted (IFN-gamma(-/-)) mice. It has been reported that IFN-gamma is not required for recovery from primary infection with influenza virus but is important for HSI. Here, we conclusively show that IFN-gamma is not required for induction of secondary influenza virus-specific CTL responses in mediastinal lymph nodes and HSI to lethal influenza A virus infection. Although T helper 2 (Th2)-type cytokines were upregulated in the lungs of IFN-gamma(-/-) mice after virus challenge, either Th1- or Th2-biased responses could provide heterosubtypic protection. Furthermore, titers of serum-neutralizing and cross-reactive antibodies to conserved nucleoprotein in IFN-gamma(-/-) mice did not differ significantly from those in immunocompetent mice. These results indicate that lack of IFN-gamma does not impair cross-reactive virus-specific immune responses and HSI to lethal infection with influenza virus. Our findings provide new insight for the mechanisms of HSI and should be valuable in the development of protective mucosal vaccines against variant virus strains, such as influenza and human immunodeficiency virus.     

The role of alpha/beta and gamma interferons in development of immunity to influenza A virus in mice

During influenza virus infection innate and adaptive immune defenses are activated to eliminate the virus and thereby bring about recovery from illness. Both arms of the adaptive immune system, antibody neutralization of free virus and termination of intracellular virus replication by antiviral cytotoxic T cells (CTLs), play pivotal roles in virus elimination and protection from disease. Innate cytokine responses, such as alpha/beta interferon (IFN-alpha/beta) or IFN-gamma, can have roles in determining the rate of virus replication in the initial stages of infection and in shaping the initial inflammatory and downstream adaptive immune responses. The effect of these cytokines on the replication of pneumotropic influenza A virus in the respiratory tract and in the regulation of adaptive antiviral immunity was examined after intranasal infection of mice with null mutations in receptors for IFN-alpha/beta, IFN-gamma, and both IFNs. Virus titers in the lungs of mice unable to respond to IFNs were not significantly different from congenic controls for both primary and secondary infection. Likewise the mice were comparably susceptible to X31 (H3N2) influenza virus infection. No significant disruption to the development of normal antiviral CTL or antibody responses was observed. In contrast, mice bearing the disrupted IFN-alpha/beta receptor exhibited accelerated kinetics and significantly higher levels of neutralizing antibody activity during primary or secondary heterosubtypic influenza virus infection. Thus, these observations reveal no significant contribution for IFN-controlled pathways in shaping acute or memory T-cell responses to pneumotropic influenza virus infection but do indicate some role for IFN-alpha/beta in the regulation of antibody responses. Recognizing the pivotal role of CTLs and antibody in virus clearance, it is reasonable to assume a redundancy in IFN-mediated antiviral effects in pulmonary influenza. However, IFN-alpha/beta seems to be a valid factor in determining tissue tropism and replicative rates of highly virulent influenza virus strains as reported previously by others, and this aspect is discussed here.     

In vivo blockade of gamma interferon affects the influenza virus-induced humoral and the local cellular immune response in lung tissue.

Influenza virus infection induces the local production of gamma interferon (IFN-gamma) by T cells and non-T cells in the respiratory tract. To elucidate the possible functions of this cytokine, the humoral and local cellular immune responses to influenza virus were studied in BALB/c mice with or without in vivo neutralization of IFN-gamma by using monoclonal antibodies. Neutralization of IFN-gamma led to a significant reduction in virus-specific titers of immunoglobulins G2a and G3 in serum but had little effect on other isotypes. Studies on cells isolated from the lung parenchyma itself revealed that at the height of the immune response the ability of these cells to produce cytokines after antigen or T-cell receptor/CD3 stimulation was not affected. Ex vivo cytolytic activity by lung parenchyma cells, which is induced by infection with this virus in normal mice, was also found to be undisturbed by this treatment, even though anti-IFN-gamma antibody activity was recovered from lung lavage samples and sera at all days studied. Surprisingly, in vivo neutralization of IFN-gamma led to a significant reduction in the magnitude of the cellular infiltrate in the lung tissue which followed infection, suggesting an involvement of IFN-gamma in the mechanisms that regulate increased leucocyte traffic in the inflamed lung parenchyma. This conclusion was supported by findings of differences between mock-treated and anti-IFN-gamma-treated mice in the number of CD8+ lung T cells expressing CD49d (alpha4-integrin) and CD62L at various times after influenza virus infection. This study therefore demonstrates that IFN-gamma affects the local cellular response in the respiratory tract as well as the systemic humoral response to influenza virus infection.     

New Class of Monoclonal Antibodies against Severe Influenza: Prophylactic and Therapeutic Efficacy in Ferrets

Background

The urgent medical need for innovative approaches to control influenza is emphasized by the widespread resistance of circulating subtype H1N1 viruses to the leading antiviral drug oseltamivir, the pandemic threat posed by the occurrences of human infections with highly pathogenic avian H5N1 viruses, and indeed the evolving swine-origin H1N1 influenza pandemic. A recently discovered class of human monoclonal antibodies with the ability to neutralize a broad spectrum of influenza viruses (including H1, H2, H5, H6 and H9 subtypes) has the potential to prevent and treat influenza in humans. Here we report the latest efficacy data for a representative antibody of this novel class.

Methodology/Principal Findings

We evaluated the prophylactic and therapeutic efficacy of the human monoclonal antibody CR6261 against lethal challenge with the highly pathogenic avian H5N1 virus in ferrets, the optimal model of human influenza infection. Survival rates, clinically relevant disease signs such as changes in body weight and temperature, virus replication in lungs and upper respiratory tract, as well as macro- and microscopic pathology were investigated. Prophylactic administration of 30 and 10 mg/kg CR6261 prior to viral challenge completely prevented mortality, weight loss and reduced the amount of infectious virus in the lungs by more than 99.9%, abolished shedding of virus in pharyngeal secretions and largely prevented H5N1-induced lung pathology. When administered therapeutically 1 day after challenge, 30 mg/kg CR6261 prevented death in all animals and blunted disease, as evidenced by decreased weight loss and temperature rise, reduced lung viral loads and shedding, and less lung damage.

Conclusions/Significance

These data demonstrate the prophylactic and therapeutic efficacy of this new class of human monoclonal antibodies in a highly stringent and clinically relevant animal model of influenza and justify clinical development of this approach as intervention for both seasonal and pandemic influenza.     

Role of endogenous tumor necrosis factor alpha and gamma interferon in resistance to Corynebacterium pseudotuberculosis infection in mice

The production and roles of endogenous tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) in the infection of Corynebacterium (C.) pseudotuberculosis were investigated in mice. The maximum levels of TNF-alpha and IFN-gamma were detected on day 4 after infection. The administration of anti-TNF-alpha monoclonal antibody (mAb) as well as anti-IFN-gamma mAb increased bacterial proliferation in the organs, leading to the death of infected mice, but anti-IFN-gamma mAb showed a less marked effect than anti-TNF-alpha mAb. The suppressive effect of anti-TNF-alpha and anti-IFN-gamma mAbs on anticorynebacterial resistance was augmented by the simultaneous administration of these antibodies. Anti-TNF-alpha mAb was found to be highly effective when administered on day 0 and day 4, suggesting that TNF-alpha produced during the early stage of infection is critical for the generation of resistance. Histologically, many microabscesses, severe follicular swelling and lymphocyte destruction were observed in mice treated with anti-TNF-alpha or anti-IFN-gamma mAb. Injection of anti-CD4 or anti-CD8 mAb also resulted in significantly increased mortality and a marked suppression of IFN-gamma production, but had no effect on TNF-alpha production. Carrageenan also showed a marked effect on the exacerbation of infection. Taken together, these results suggest that endogenously produced TNF-alpha and IFN-gamma are both essential to the host defense against C. pseudotuberculosis infection and that these cytokines may have an additive effect.     

Combination Effects of Peramivir and Favipiravir against Oseltamivir-Resistant 2009 Pandemic Influenza A(H1N1) Infection in Mice

Antiviral drugs are being used for therapeutic purposes against influenza illness in humans. However, antiviral-resistant variants often nullify the effectiveness of antivirals. Combined medications, as seen in the treatment of cancers and other infectious diseases, have been suggested as an option for the control of antiviral-resistant influenza viruses. Here, we evaluated the therapeutic value of combination therapy against oseltamivir-resistant 2009 pandemic influenza H1N1 virus infection in DBA/2 mice. Mice were treated for five days with favipiravir and peramivir starting 4 hours after lethal challenge. Compared with either monotherapy, combination therapy saved more mice from viral lethality and resulted in increased antiviral efficacy in the lungs of infected mice. Furthermore, the synergism between the two antivirals, which was consistent with the survival outcomes of combination therapy, indicated that favipiravir could serve as a critical agent of combination therapy for the control of oseltamivir-resistant strains. Our results provide new insight into the feasibility of favipiravir in combination therapy against oseltamivir-resistant influenza virus infection.     

Triazavirin prophylactic efficacy against influenza virus A (H5N1)

The experimental study of the prophylactic efficacy of Triazaverin against the experimental form of the influenza virus A (H5N1) on albino mice intranasally infected with the influenza virus A/Chicken/Kurgan/Russia/02/05 vs. the reference drugs Tamiflu, Remantadin and Arbidol showed that in doses of 1 to 100 mg/kg it was efficient in the animal protection from death. The drug was also efficient in the urgent prophylaxis. Triazaverin effectively inhibited the influenza A virus multiplication in the lungs of the albino mice.     

Enhanced virus replication and inhibition of lymphocytic choriomeningitis virus disease in anti-gamma interferon-treated mice.

The role of gamma interferon (IFN-gamma) induced during a viral infection in the ability of the host to acquire antiviral immunity was studied in mice. They were injected subcutaneously daily with an ammonium sulfate-precipitated sheep anti-IFN-gamma antibody preparation able to neutralize 10(4) U of IFN-gamma. Specificity of the anti-IFN-gamma antiserum was demonstrated by absence of detectable activity against natural IFN-alpha and -beta. Controls were treated with a similarly prepared normal sheep serum. Treatment with the IFN-gamma-specific antibody preparation had no influence on the ability of mice to generate anti-vaccinia virus- or anti-vesicular stomatitis virus (VSV)-specific cytotoxic T-cell (CTL) responses or T helper-dependent immunoglobulin G responses to VSV. In contrast, treatment of mice with sheep anti-IFN-gamma impaired CTL responses against lymphocytic choriomeningitis (LCM) virus (LCMV, Aggressive isolate); in addition, under the experimental conditions used, it prevented lethal LCM. Cytotoxic T-cell activity measured in the spleens of anti-IFN-gamma-treated mice was comparable to that found in mice initially infected with a 100-fold-larger dose of LCMV. Evaluation of the effects of treatment on the kinetics of virus replication revealed that in both euthymic and athymic nude C57BL/6 mice, anti-IFN-gamma treatment led to an increase of virus titers up to 100-fold compared with control mice. Therefore, IFN-gamma may play a role in controlling viruses with tropism for lymphocytes and monocytes/macrophages, such as LCMV.     

小鼠感染合胞病毒与鼠流感病毒后肺脏病理学比较研究

目的与方法用合胞病毒(RSV)和鼠肺流感病毒(IVP)感染SPF级BALB/c小鼠,复制两种不同的小鼠病毒性肺炎动物模型,观察其临床症状,并对两种模型各自的肺部组织病理学特点进行研究。结果与结论IVP模型组与RSV模型组小鼠感染病毒后,分别在试验的2天和3天发病,临床症状均表现为精神沉郁、耸毛、卷缩、毛无光泽、活动减少、呼吸急促、咳嗽。但IVP感染模型组小鼠在发病后出现死亡,第7天其死亡率达到40%,而RSV感染模型组小鼠7日试验内无死亡病例发生。病理组织学诊断,RSV模型组小鼠为急性渗出性间质性肺炎,IVP模型组小鼠为出血性间质性肺炎。     

DBA/2 mouse as an animal model for anti-influenza drug efficacy evaluation

Influenza viruses are seasonally recurring human pathogens. Vaccines and antiviral drugs are available for influenza. However, the viruses, which often change themselves via antigenic drift and shift, demand constant efforts to update vaccine antigens every year and develop new agents with broad-spectrum antiviral efficacy. An animal model is critical for such efforts. While most human influenza viruses are unable to kill BALB/c mice, some strains have been shown to kill DBA/2 mice without prior adaptation. Therefore, in this study, we explored the feasibility of employing DBA/2 mice as a model in the development of anti-influenza drugs. Unlike the BALB/c strain, DBA/2 mice were highly susceptible and could be killed with a relatively low titer (50% DBA/2 lethal dose = 10^2.83 plaque-forming units) of the A/Korea/01/2009 virus (2009 pandemic H1N1 virus). When treated with a neuraminidase inhibitor, oseltamivir phosphate, infected DBA/2 mice survived until 14 days post-infection. The reduced morbidity of the infected DBA/2 mice was also consistent with the oseltamivir treatment. Taking these data into consideration, we propose that the DBA/2 mouse is an excellent animal model to evaluate antiviral efficacy against influenza infection and can be further utilized for combination therapies or bioactivity models of existing and newly developed anti-influenza drugs.     

IFN mimetic as a therapeutic for lethal vaccinia virus infection: possible effects on innate and adaptive immune responses

We have developed small peptide mimetics of IFN-gamma that can bypass the poxvirus virulence factor B8R protein, which binds to intact IFN-gamma and prevents its interaction with receptor extracellular domain. Thus, these peptides inhibit vaccinia virus replication in cell culture where intact IFN-gamma is ineffective. We demonstrate here that the mouse IFN-gamma-mimetic peptide, IFN-gamma(95-132), protects C57BL/6 mice against overwhelming lethal vaccinia virus infection. The mimetic peptide was synthesized with an attached lipophilic group for penetration of cell plasma membrane. Injection of mimetic i.p. before and at the time of intranasal (10(6) PFU) or i.p. (10(7) PFU) challenge with virus resulted in complete protection at 200 microg of mimetic and 40-60% protection at 5 microg of mimetic. Initiation of treatment of mice with IFN-gamma mimetic up to 2 days postinfection resulted in complete protection against death, whereas initiation of treatment at 6 days postinfection resulted in 40% protection. Administration of mimetic by the oral route also completely protected mice against the intranasal route of a lethal dose of vaccinia virus challenge. In addition to its direct antiviral effect, the mimetic also possessed adjuvant effects in boosting humoral and cellular immunity to vaccinia virus. The combination of antiviral and adjuvant effects by the IFN mimetic probably plays a role in its potent anti-vaccinia virus properties. These results suggest an effective therapeutic against ongoing, lethal poxvirus infections that taps into innate and adaptive host defenses.     

In vivo antiviral effect of interleukin 18 in a mouse model of vaccinia virus infection.

Interleukin-18 (IL-18), originally called interferon-gamma (IFN-gamma)-inducing factor is a novel cytokine which exhibits pleiotropic immunomodulatory activities such as the activation of natural killer (NK) cells and cytotoxic T lymphocytes (CTL). In this study, the efficacy of IL-18 on viral infection in mice was investigated. IL-18 treatment significantly suppressed pock formation on the tails of BALB/c mice inoculated intravenously with vaccinia virus when the cytokine was administered intraperitoneally on days 0, 2 and 4 after infection. Sequentially, NK and CTL activity of the infected mice were significantly augmented by IL-18 injection. The in vivo anti-vaccinia virus activity of IL-18 was only partially inhibited by treating the infected mice with anti-asialo GM1 antibody. When infected mice were injected with anti-IFN-gamma antibody only, severe deterioration of health and significant body weight loss were observed, suggesting that IFN-gamma is very important in protecting mice against vaccinia virus infection. Interestingly, IL-18 injection visibly improved the severe vaccinia virus-induced symptoms in mice treated with anti-IFN-gamma antibody, even though a pivotal involvement of IFN-gamma in IL-18-mediated anti-vaccinia virus effect is not yet determined. Taken together, these results indicate that the IL-18-elicited anti-vaccinia virus effect in the acute phase of infection would be raised by the sum of various host defence mechanisms including NK cells and CTL, and not from a specific immunocompetent cell population or effector molecule.     

Antiviral activity of 3,4’-dihydroxyflavone on influenza a virus

Influenza virus infection causes thousands of deaths and millions of hospitalizations worldwide every year and the emergence of resistance to anti-influenza drugs has prompted scientists to seek new natural antiviral materials. In this study, we screened 13 different flavonoids from various flavonoid groups to identify the most potent antiviral flavonoid against human influenza A/PR/8/34 (H1N1). The 3-hydroxyl group flavonoids, including 3,2?dihydroxyflavone (3,2?DHF) and 3,4?dihydroxyflavone (3,4?DHF), showed potent anti-influenza activity. They inhibited viral neuraminidase activity and viral adsorption onto cells. To confirm the anti-influenza activity of these flavonoids, we used an in vivo mouse model. In mice infected with human influenza, oral administration of 3,4?DHF significantly decreased virus titers and pathological changes in the lung and reduced body weight loss and death. Our data suggest that 3-hydroxyl group flavonoids, particularly 3,4?DHF, have potent antiviral activity against human influenza A/PR/8/34 (H1N1) in vitro and in vivo. Further clinical studies are needed to investigate the therapeutic and prophylactic potential of the 3-hydroxyl group flavonoids in treating influenza pandemics.     

Gamma interferon is not essential for recovery from acute infection with murine gammaherpesvirus 68.

Murine gammaherpesvirus 68 (MHV-68) when administered intranasally induces high levels of gamma interferon (IFN-gamma) in the lymphoid tissues of infected mice. In order to investigate the role of this cytokine in the immune response to MHV-68, mice which were congenitally deficient in the IFN-gamma gene (IFN-gamma knockout mice) were infected with the virus. Comparison of the courses of the disease in wild-type control and IFN-gamma knockout mice revealed surprisingly little difference. Both groups of mice had cleared infectious virus from the lungs 15 days after infection, although there did appear to be a slight delay in viral clearance in the IFN-gamma knockout mice. In addition, after the initial phase of viral clearance, the lungs of both groups remained clear of replicating virus throughout the course of the experiment, which concluded 34 days after infection. Consistent with these observations, cytotoxic T-cell activities were similar in the two groups of mice. Levels of latent virus were comparable in wild-type and knockout mice over the time course studied. Furthermore, analysis of the numbers, types, and activation status of cells in the lungs, lymph nodes, and spleens of control and knockout mice revealed no striking difference. This suggests that IFN-gamma is not essential for regulating the cell recruitment or proliferation that normally occurs during this viral infection. Apart from the expected lack of IFN-gamma, cytokine profiles were not dramatically altered in IFN-gamma knockout mice, demonstrating that IFN-gamma did not suppress the proliferation or differentiation of Th2 cells during MHV-68 infection. These observations indicate that IFN-gamma plays a nonessential or redundant role in the control of acute infection with MHV-68.     

Production of lipopolysaccharide-induced tumour necrosis factor during influenza virus infection in mice coincides with viral replication and respiratory oxidative burst

Increased morbidity and mortality occur regularly during influenza epidemics. The exact mechanisms involved are not well defined but bacterial superinfection of influenza virus infected patients is considered to play an important role. In the present study, the effect of influenza virus infection on in vivo production of turnout necrosis factor (TNF) in response to bacterial stimuli was investigated. Release of TNF in mice infected by an aerosol of influenza virus was significant after administration of bacterial lipopolysaccharide (LPS) at 72 h, whereas administration of homologous influenza virus produced only modest amounts of TNF at 96 h. Significant production of TNF was observed 48 h after intravenous administration of infectious influenza in response to LPS but not with the homologous virus. TNF induced after influenza virus infection could be blocked by a specific murine anti-TNF monoclonal antibody. Higher TNF production following aerosol influenza infection correlated with peak titres of influenza virus in the lungs of infected mice and with enhanced generation of luminoldependent chemiluminscence.