transforming-growth-factor-beta and Influenza--Human

The efficacy and effectiveness of influenza vaccines depend primarily on the vaccine recipient and the virus similarity to the endemic virus. Regulatory T cells (Tregs) and cytokines are known to restrict immune responses against viral infections. We conducted this study to explore the role of Tregs, cytokines, and antibody production after influenza vaccination. The whole blood was collected from healthy subjects (n = 36) before and two weeks after influenza vaccine immunization for two or three consecutive years. The cell surface markers, intracellular staining of Foxp3(+) Tregs, and Th1/Th2 cytokines were determined. The antibody titer was detected using the hemagglutination inhibition test. The CD3(+), CD127(+), CD4(+)CD25(+) and CD4(+)Foxp3(+) cells were increased significantly post vaccination. The plasma level of the transforming growth factor (TGF-β), but not interleukin (IL)-2, IL-4, IL-5, IL-10, IFN-γ, TNF-α, was also found to increase significantly after vaccination. We further correlated the cytokine fold-increases with the anti-influenza antibody titer for individual post vaccination. It was found that the IL-10 level after vaccination correlated with the fold-increases of anti-H1N1, anti-H3N2, anti-B/Yamagata, and anti-B/Victoria antibodies. But, a negative relationship occurs between the TGF-β level and fold-increases of anti-H1N1, anti-H3N2, anti-B/Yamagata, and anti-B/Victoria antibodies post vaccination. Treg cells and TGF-β seem to participate in the downregulation of the anti-influenza antibody response post influenza vaccination. Alteration of Treg activity might enhance influenza vaccine antibody responses and efficacy.

Topics: Adult; Antibodies, Viral; CD4-Positive T-Lymphocytes; Female; Forkhead Transcription Factors; Humans; Influenza Vaccines; Influenza, Human; Interleukin-10; Interleukin-4; Interleukin-5; Male; Middle Aged; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Young Adult

Influenza A virus (IAV) predisposes individuals to often more severe secondary bacterial infections with Streptococcus pneumonia (S. pneumoniae). The outcomes of these infections may be made worse with the increase in antimicrobial resistance and a lack of new treatments to combat this. Th17 responses are crucial in clearing S. pneumoniae from the lung. We previously demonstrated that early IAV infection of human monocytes significantly reduced levels of S. pneumoniae-driven cytokines involved in the Th17 response. Here, we have further identified that IAV targets specific TLRs (TLR2, TLR4, TLR9) involved in sensing S. pneumoniae infection resulting, in a reduction in TLR agonist-induced IL-23 and TGF-β. The effect of IAV is more profound on the TLR2 and TLR9 pathways. We have established that IAV-mediated inhibition of TLR9-induction is related to a downregulation of RORC, a Th17 specific transcription factor. Other studies using mouse models demonstrated that TLR5 agonism improved the efficacy of antibiotics in the treatment of IAV/S. pneumoniae co-infections. Therefore, we investigated if TLR5 agonism could restore inhibited Th17 responses in human monocytes. Levels of pneumococcus-driven cytokines, which had previously been inhibited by IAV were not reduced in the presence of the TLR5 mono-agonist, suggesting that such treatment may overcome IAV inhibition of Th17 responses. The importance of our research is in demonstrating the IAV directly targets S. pneumoniae-associated TLR pathways. Additionally, the IAV-inhibition of Th17 responses can be restored by TLR5 agonism, which indicates that there may be a different Th17 signalling pathway which is not affected by IAV infection.

Topics: Humans; Immunity; Influenza A virus; Influenza, Human; Monocytes; Nuclear Receptor Subfamily 1, Group F, Member 3; Reproducibility of Results; Signal Transduction; Streptococcus pneumoniae; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptor 5; Transforming Growth Factor beta

SARS-CoV-2 is a single-stranded RNA virus that causes COVID-19. Given its acute and often self-limiting course, it is likely that components of the innate immune system play a central part in controlling virus replication and determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses

Topics: Atlases as Topic; COVID-19; Gene Expression Regulation; Humans; Immunity, Innate; Influenza, Human; Killer Cells, Natural; RNA-Seq; SARS-CoV-2; Single-Cell Analysis; Time Factors; Transforming Growth Factor beta; Viral Load; Virus Replication

Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-β is intimately involved in the fibrogenic process. When activated, TGF-β promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-β1 tissue expression) involved in the TGF-β1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-β1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-β pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-β inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.

Topics: Actins; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme 2; Caveolin 1; Collagen Type I; Collagen Type III; COVID-19; COVID-19 Drug Treatment; Female; Humans; Hyaluronan Receptors; Immunohistochemistry; Influenza A Virus, H1N1 Subtype; Influenza, Human; Interleukin-4; Male; Matrix Metalloproteinase 9; Middle Aged; Proto-Oncogene Proteins c-akt; Pulmonary Fibrosis; Retrospective Studies; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1

It is well known that supplemental oxygen used to treat preterm infants in respiratory distress is associated with permanently disrupting lung development and the host response to influenza A virus (IAV). However, many infants who go home with normally functioning lungs are also at risk for hyperreactivity after a respiratory viral infection. We recently reported a new, low-dose hyperoxia mouse model (40% for 8 days; 40×8) that causes a transient change in lung function that resolves, rendering 40×8 adult animals functionally indistinguishable from room air controls. Here we report that when infected with IAV, 40×8 mice display an early transient activation of TGFβ signaling and later airway hyperreactivity associated with peribronchial inflammation (profibrotic macrophages) and fibrosis compared with infected room air controls, suggesting neonatal oxygen induced hidden molecular changes that prime the lung for hyperreactive airways disease. Although searching for potential activators of TGFβ signaling, we discovered that thrombospondin-1 (TSP-1) is elevated in naïve 40×8 mice compared with controls and localized to lung megakaryocytes and platelets before and during IAV infection. Elevated TSP-1 was also identified in human autopsy samples of former preterm infants with bronchopulmonary dysplasia. These findings reveal how low doses of oxygen that do not durably change lung function may prime it for hyperreactive airways disease by changing expression of genes, such as TSP-1, thus helping to explain why former preterm infants who have normal lung function are susceptible to airway obstruction and increased morbidity after viral infection.

Topics: Animals; Bronchial Hyperreactivity; Bronchopulmonary Dysplasia; Cell Line; Disease Models, Animal; Dogs; Female; Humans; Hyperoxia; Influenza A virus; Influenza, Human; Madin Darby Canine Kidney Cells; Male; Mice; Mice, Inbred C57BL; Orthomyxoviridae Infections; Pulmonary Fibrosis; Thrombospondin 1; Transforming Growth Factor beta

Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8

Topics: Age Factors; Animals; CD8-Positive T-Lymphocytes; COVID-19; Host-Pathogen Interactions; Humans; Immunologic Memory; Influenza, Human; Lung; Mice, Inbred C57BL; Orthomyxoviridae; Orthomyxoviridae Infections; Pandemics; Pneumonia, Viral; SARS-CoV-2; Transforming Growth Factor beta

This study aimed to investigate whether the human antigen presenting cells (APCs) can process and present Salmonella expressing H7N9 hemagglutinin (Sal-HA), neuraminidase (Sal-NA) or M2 ectodomain (Sal-M2e) to T cells and subsequently activate CD4

Topics: Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens, Viral; CD4-Positive T-Lymphocytes; Cell Proliferation; Coculture Techniques; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Immunity, Cellular; Influenza A Virus, H7N9 Subtype; Influenza, Human; Interferon-gamma; Interleukins; Mitomycin; Neuraminidase; Primary Cell Culture; Recombinant Proteins; Salmonella typhimurium; Transforming Growth Factor beta; Viral Matrix Proteins

Topics: Animals; Asthma; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Coinfection; Disease Models, Animal; Disease Susceptibility; Humans; Influenza A virus; Influenza, Human; Interferon-gamma; Mice, Inbred BALB C; Mice, Inbred C57BL; Pneumococcal Infections; Streptococcus pneumoniae; Survival Analysis; Transforming Growth Factor beta

Intranasal inoculation with influenza hemagglutinin subunit with polyinosine-polycytidylic (polyI:C), a synthetic analog for double-stranded RNA, enhances production of vaccine-specific immunoglobulin (Ig) A, which is superior to IgG in prophylactic immunity. The mechanism whereby polyI:C skews to IgA production in the nasal-associated lymph tissue (NALT) was investigated in mouse models. Nasally instilled polyI:C was endocytosed into CD103

Topics: Animals; Antigens, CD; Basic-Leucine Zipper Transcription Factors; Cells, Cultured; Dendritic Cells; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Immunity, Humoral; Immunoglobulin A; Influenza A Virus, H1N1 Subtype; Influenza Vaccines; Influenza, Human; Integrin alpha Chains; Lymphoid Tissue; Mice; Mice, Knockout; Nose; Orthomyxoviridae Infections; Poly I-C; Repressor Proteins; Signal Transduction; Toll-Like Receptor 3; Transforming Growth Factor beta; Vaccination

Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-β (TGF-β) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-β. In the current study, we examine the contribution of TGF-β activity to the GC-resistance caused by viral infection. We demonstrate that viral infection of human bronchial epithelial cells with RSV, RV or IAV impairs GC anti-inflammatory action. Poly(I:C), a synthetic analog of double-stranded RNA, also impairs GC activity. Both viral infection and poly(I:C) increase TGF-β expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGFβRI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-β activity associated with viral infection. This study shows for the first time that viral-induced glucocorticoid-insensitivity is partially mediated by activation of endogenous TGF-β.

Topics: Anti-Inflammatory Agents; Antiviral Agents; Asthma; Benzamides; Cell Line; Dioxoles; Drug Resistance, Viral; Enzyme Activation; Epithelial Cells; Glucocorticoids; Humans; Influenza A virus; Influenza, Human; ortho-Aminobenzoates; Picornaviridae Infections; Poly I-C; Protein Serine-Threonine Kinases; Pulmonary Disease, Chronic Obstructive; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Respiratory Mucosa; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Rhinovirus; Transforming Growth Factor beta

Influenza infection predisposes the host to secondary bacterial pneumonia, which is a major cause of mortality during influenza epidemics. The molecular mechanisms underlying the bacterial coinfection remain elusive. Neuraminidase (NA) of influenza A virus (IAV) enhances bacterial adherence and also activates TGF-β. Because TGF-β can up-regulate host adhesion molecules such as fibronectin and integrins for bacterial binding, we hypothesized that activated TGF-β during IAV infection contributes to secondary bacterial infection by up-regulating these host adhesion molecules. Flow cytometric analyses of a human lung epithelial cell line indicated that the expression of fibronectin and α5 integrin was up-regulated after IAV infection or treatment with recombinant NA and was reversed through the inhibition of TGF-β signaling. IAV-promoted adherence of group A Streptococcus (GAS) and other coinfective pathogens that require fibronectin for binding was prevented significantly by the inhibition of TGF-β. However, IAV did not promote the adherence of Lactococcus lactis unless this bacterium expressed the fibronectin-binding protein of GAS. Mouse experiments showed that IAV infection enhanced GAS colonization in the lungs of wild-type animals but not in the lungs of mice deficient in TGF-β signaling. Taken together, these results reveal a previously unrecognized mechanism: IAV NA enhances the expression of cellular adhesins through the activation of TGF-β, leading to increased bacterial loading in the lungs. Our results suggest that TGF-β and cellular adhesins may be potential pharmaceutical targets for the prevention of coinfection.

Topics: Animals; Bacterial Adhesion; Cell Adhesion Molecules; Coinfection; Colony Count, Microbial; Epithelial Cells; Fibronectins; Humans; Influenza A virus; Influenza, Human; Lung; Mice; Models, Biological; Neuraminidase; Orthomyxoviridae Infections; Protein Binding; Receptors, Cell Surface; Recombinant Proteins; Signal Transduction; Streptococcal Infections; Streptococcus pyogenes; Transforming Growth Factor beta

During pregnancy, immunological and hormonal alterations place women at increased risk for influenza-related severe illnesses including hospitalization and death. Although A(H1N1) pdm09 infection resulted in increased disease severity in pregnant women, the precise mechanisms responsible for this risk have yet to be established.. The present study was aimed to investigate the role of host chemokines and cytokine profiles in A(H1N1) pdm09 infection regarding disease severity in pregnant women.. This retrospective survey examined 41 pregnant women with confirmed A(H1N1) pdm09 infection. Of them, 12 died (D), 29 survived (S), and 17 remained uninfected and served as controls (C). Antiviral response was evaluated for IFN-β expression and gene expression profiles of cytokines (TNF-α, IL-6, IL-12, TGF-β) and chemokines (IL-8, RANTES, MCP-1, IP-10), and the viral Matrix (M1) gene was quantified and normalized using the housekeeping gene product β-actin mRNA.. Higher IL-8 and TNF-α mRNA expression were found in D and S compared with C, while IL-6 showed higher expression in D. Interestingly, these results were associated with a decrease in the anti-inflammatory response of TGF-β mRNA and IFN-β. These alterations would lead to an imbalance in the immune response of those patients.. Pregnancy-related reductions in IFN-β and TGF-β expression levels and elevated levels of pro-inflammatory cytokines could explain the increased severity of infection and death of pregnant women. These findings may help improve the understanding of the high susceptibility and disease severity to influenza virus infection during pregnancy.

Topics: Adult; Chemokines; Cytokines; Female; Gene Expression Profiling; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Interferon-beta; Interleukin-6; Interleukin-8; Pregnancy; Pregnancy Complications, Infectious; Retrospective Studies; Severity of Illness Index; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

There is a strong interest in finding adequate biomarkers to aid in the diagnosis and prognosis of influenza A (H1N1)pdm09 virus infection. In this study, serum levels of inflammatory cytokines and laboratory markers were evaluated to assess their usefulness as biomarkers of influenza A (H1N1)pdm09 and their association with fatal cases. Serum samples of consecutive patients with a clinical presentation suggestive of influenza A (H1N1)pdm09 and progression to sepsis were evaluated. Serum inflammatory cytokines and routine laboratory tests were performed and correlated with positivity for influenza A (H1N1)pdm09 influenza by real time reverse transcription polymerase chain reaction and the results of three clinical severity scores (Sequential Organ Failure Assessment [SOFA], CURB-65, and Acute Physiology and Chronic Health Evaluation II [APACHE II]). High SOFA scores and some of its individual components, but not CURB-65 or APACHE II scores, correlate with fatal cases regardless of etiology. Total and unconjugated bilirubin, Ca(++), Cl(-), prothrombin times, and partial thromboplastin times discriminate influenza A (H1N1)pdm09 from other causes of community-acquired pneumonia. High levels of IL-8, IL-10, and IL-17 were increased in influenza A (H1N1)pdm09 patients when compared with controls (p<0.05). IL-6 levels were significantly elevated in influenza A (H1N1)pdm09 patients and non-(H1N1)pdm09 patients when compared with controls (p<0.05). TGF-β serum levels discern between healthy controls, influenza A (H1N1)pdm09 patients, and patients with other causes of community-acquired pneumonia. TGF-β levels were negatively correlated with SOFA on admission in influenza A (H1N1)pdm09 patients. TGF-β levels are a useful tool for differentiating influenza A (H1N1)pdm09 from other causes of pneumonia progressing to sepsis.

Topics: Adult; Bilirubin; Biomarkers; Community-Acquired Infections; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Interleukin-10; Interleukin-17; Interleukin-6; Interleukin-8; Male; Partial Thromboplastin Time; Pneumonia; Prothrombin Time; Reverse Transcriptase Polymerase Chain Reaction; Sepsis; Severity of Illness Index; Transforming Growth Factor beta

The 2009 influenza A(H1N1) pandemic led to a particularly high risk of morbidity and mortality among pregnant women. Therefore, inactivated influenza vaccines have been widely recommended for women in any period of gestation. Recent studies have shown that the peripheral adaptive immune system plays an important role in the function of the central nervous system (CNS). The present study was conducted to explore if influenza vaccination, aiming to induce protective immune activation, affects maternal neurogenesis and cognitive ability. The results showed that A(H1N1) pregnant mice (AIV+Pre) had superior spatial working memory performance compared with pregnant controls (Pre). At the cellular level, a transient increase in both cell proliferation and neuronal differentiation in the dentate gyrus (DG) was found in the AIV+Pre group compared with the Pre group when BrdU was injected on gestational day 14 (G14). However, there were no obvious differences between A(H1N1) virgin mice (AIV+Vir) and virgin controls (Vir) in both hippocampal neurogenesis and working memory. Our findings further indicated that prolactin (PRL) concentrations were not overtly different between the AIV+Pre group and the Pre group at any time. Interestingly, IL-4 and IFN-γ levels were obviously increased both in the serum and hippocampus of the AIV+Pre group (with a T helper-1 like response; Th1) compared with the Pre group (with a T helper-2 like response; Th2) at G14, whereas the expression of IL-6 and TNF-α, the proinflammatory factors, was significantly reduced. Altogether, the results suggest that A(H1N1) vaccination during early pregnancy may contribute to adult hippocampal neurogenesis and spatial working memory and that the improvements were, at least in part, associated with Th1/Th2 balance.

Topics: Animals; Antibodies, Viral; Brain-Derived Neurotrophic Factor; Female; Hippocampus; Humans; Influenza A Virus, H1N1 Subtype; Influenza Vaccines; Influenza, Human; Interferon-gamma; Interleukin-4; Interleukin-6; Maze Learning; Memory, Short-Term; Mice, Inbred C57BL; Neurogenesis; Pregnancy; Prolactin; Random Allocation; Th1-Th2 Balance; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vaccination; Vaccines, Inactivated

Chronic heat stress (CHS) is known to have negative impacts on the immune responses in animals and increases their susceptibility to infections including the highly pathogenic avian influenza virus H5N1. However, the role of regulatory T cells (Tregs) in CHS immunosuppression remains largely undefined. In this study, we demonstrated a novel mechanism by which CHS suppressed both Th1 and Th2 immune responses and dramatically decreased the protective efficacy of the formalin-inactivated H5N1 vaccine against H5N1 influenza virus infection. This suppression was found to be associated with the induced generation of CD4⁺ CD25⁺ Foxp3⁺ Tregs and the increased secretions of IL-10 and TGF- β in CD4⁺ T cells. Adoptive transfer of the induced Tregs also suppressed the protective efficacy of formalin-inactivated H5N1 virus immunization. Collectively, this study identifies a novel mechanism of CHS immunosuppression mediated by regulating CD4⁺ CD25⁺ Foxp3⁺ Tregs.

Topics: CD4-Positive T-Lymphocytes; Forkhead Transcription Factors; Heat-Shock Response; Hot Temperature; Humans; Immunosuppression Therapy; Influenza A Virus, H5N1 Subtype; Influenza, Human; Interleukin-2 Receptor alpha Subunit; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Vaccination

Transforming growth factor-beta (TGF-β), a multifunctional cytokine regulating several immunologic processes, is expressed by virtually all cells as a biologically inactive molecule termed latent TGF-β (LTGF-β). We have previously shown that TGF-β activity increases during influenza virus infection in mice and suggested that the neuraminidase (NA) protein mediates this activation. In the current study, we determined the mechanism of activation of LTGF-β by NA from the influenza virus A/Gray Teal/Australia/2/1979 by mobility shift and enzyme inhibition assays. We also investigated whether exogenous TGF-β administered via a replication-deficient adenovirus vector provides protection from H5N1 influenza pathogenesis and whether depletion of TGF-β during virus infection increases morbidity in mice. We found that both the influenza and bacterial NA activate LTGF-β by removing sialic acid motifs from LTGF-β, each NA being specific for the sialic acid linkages cleaved. Further, NA likely activates LTGF-β primarily via its enzymatic activity, but proteases might also play a role in this process. Several influenza A virus subtypes (H1N1, H1N2, H3N2, H5N9, H6N1, and H7N3) except the highly pathogenic H5N1 strains activated LTGF-β in vitro and in vivo. Addition of exogenous TGF-β to H5N1 influenza virus-infected mice delayed mortality and reduced viral titers whereas neutralization of TGF-β during H5N1 and pandemic 2009 H1N1 infection increased morbidity. Together, these data show that microbe-associated NAs can directly activate LTGF-β and that TGF-β plays a pivotal role protecting the host from influenza pathogenesis.

Topics: Animals; Cells, Cultured; Chick Embryo; Dogs; Enzyme Activation; Humans; Influenza A Virus, H5N1 Subtype; Influenza, Human; Mice; Mice, Inbred BALB C; Neuraminidase; Orthomyxoviridae Infections; Recombinant Proteins; Transforming Growth Factor beta

In 1997, an outbreak of virulent H5N1 avian influenza virus occurred in poultry in Hong Kong (HK) and was linked to a direct transmission to humans. The factors associated with transmission of avian influenza virus to mammals are not fully understood, and the potential risk of other highly virulent avian influenza A viruses infecting and causing disease in mammals is not known. In this study, two avian and one human HK-origin H5N1 virus along with four additional highly pathogenic H5 avian influenza viruses were analyzed for their pathogenicity in 6- to 8-week-old BALB/c mice. Both the avian and human HK H5 influenza virus isolates caused severe disease in mice, characterized by induced hypothermia, clinical signs, rapid weight loss, and 75 to 100% mortality by 6 to 8 days postinfection. Three of the non-HK-origin isolates caused no detectable clinical signs. One isolate, A/tk/England/91 (H5N1), induced measurable disease, and all but one of the animals recovered. Infections resulted in mild to severe lesions in both the upper and lower respiratory tracts. Most consistently, the viruses caused necrosis in respiratory epithelium of the nasal cavity, trachea, bronchi, and bronchioles with accompanying inflammation. The most severe and widespread lesions were observed in the lungs of HK avian influenza virus-infected mice, while no lesions or only mild lesions were evident with A/ck/Scotland/59 (H5N1) and A/ck/Queretaro/95 (H5N2). The A/ck/Italy/97 (H5N2) and the A/tk/England/91 (H5N1) viruses exhibited intermediate pathogenicity, producing mild to moderate respiratory tract lesions. In addition, infection by the different isolates could be further distinguished by the mouse immune response. The non-HK-origin isolates all induced production of increased levels of active transforming growth factor beta following infection, while the HK-origin isolates did not.

Topics: Animals; HN Protein; Hong Kong; Humans; Immunohistochemistry; Influenza A virus; Influenza A Virus, H5N1 Subtype; Influenza, Human; Male; Mice; Mice, Inbred BALB C; Respiratory System; Transforming Growth Factor beta; Virulence; Virus Replication

Transforming growth factor beta (TGF-beta) is a family of proteins secreted by virtually all cells in a biologically inactive form. TGF-beta levels increase during many pathophysiological situations, including viral infection. The mechanism for increased TGF-beta activity during viral infection is not understood. We observed an increase in active TGF-beta levels within 1 day in mice infected with influenza virus. Further studies showed that the neuraminidase glycoprotein of influenza A and B viruses directly activates latent TGF-beta in vitro. There are sufficient levels of TGF-beta activated by virus to induce apoptosis in cells. In addition, influenza virus-induced apoptosis is partially inhibited by TGF-beta-specific antibodies. These novel findings suggest a potential role for activation of TGF-beta during the host response to influenza virus infection, specifically apoptosis. This is the first report showing direct activation of latent TGF-beta by a viral protein.

Topics: Animals; Apoptosis; Cell Line; Chick Embryo; Dogs; Humans; Influenza A virus; Influenza B virus; Influenza, Human; Mice; Mice, Inbred BALB C; Neuraminidase; Transforming Growth Factor beta