Systematic evaluation of plasma signaling cascades by functional proteomics approaches: SARS-CoV-2 infection as model.

PURPOSE: Acute phase reactants (APRs) play a critical role in inflammation. The difference in their physiological functions or the different dynamic ranges of these proteins in plasma makes it difficult to detect them simultaneously and to use several of these proteins as a tool in clinical practice. EXPERIMENTAL DESIGN: A novel multiplex assay has been designed and optimized to carry out a high-throughput and simultaneous screening of APRs, allowing the detection of each of them at the same time and in their corresponding dynamic range. RESULTS: Using Sars-CoV-2 infection as a model, it has been possible to profile different patterns of acute phase proteins that vary significantly between healthy and infected patients. In addition, severity profiles (acute respiratory distress syndrome and sepsis) have been established. CONCLUSIONS AND CLINICAL RELEVANCE: Differential profiles in acute phase proteins can serve as a diagnostic and prognostic tool, among patient stratification. The design of this new platform for their simultaneous detection paves the way for them to be more extensive use in clinical practice.

PD-1-Expressing SARS-CoV-2-Specific CD8+ T Cells Are Not Exhausted, but Functional in Patients with COVID-19.

Memory T cell responses have been demonstrated in COVID-19 convalescents, but ex vivo phenotypes of SARS-CoV-2-specific T cells have been unclear. We detected SARS-CoV-2-specific CD8+ T cells by MHC class I multimer staining and examined their phenotypes and functions in acute and convalescent COVID-19. Multimer+ cells exhibited early differentiated effector-memory phenotypes in the early convalescent phase. The frequency of stem-like memory cells was increased among multimer+ cells in the late convalescent phase. Cytokine secretion assays combined with MHC class I multimer staining revealed that the proportion of interferon-γ (IFN-γ)-producing cells was significantly lower among SARS-CoV-2-specific CD8+ T cells than those specific to influenza A virus. Importantly, the proportion of IFN-γ-producing cells was higher in PD-1+ cells than PD-1- cells among multimer+ cells, indicating that PD-1-expressing, SARS-CoV-2-specific CD8+ T cells are not exhausted, but functional. Our current findings provide information for understanding of SARS-CoV-2-specific CD8+ T cells elicited by infection or vaccination.

iTRAQ-based quantitative proteomics reveals important host factors involved in the high pathogenicity of the H5N1 avian influenza virus in mice.

We previously reported a pair of H5N1 avian influenza viruses which are genetically similar but differ greatly in their virulence in mice. A/Chicken/Jiangsu/k0402/2010 (CK10) is highly lethal to mice, whereas A/Goose/Jiangsu/k0403/2010 (GS10) is avirulent. In this study, to investigate the host factors that account for their virulence discrepancy, we compared the pathology and host proteome of the CK10- or GS10-infected mouse lung. Moderate lung injury was observed from CK10-infected animals as early as the first day of infection, and the pathology steadily progressed at later time point. However, only mild lesions were observed in GS10-infected mouse lung at the late infection stage. Using the quantitative iTRAQ coupled LC-MS/MS method, we first found that more significantly differentially expressed (DE) proteins were stimulated by GS10 compared with CK10. However, bio-function analysis of the DE proteins suggested that CK10 induced much stronger inflammatory response-related functions than GS10. Canonical pathway analysis also demonstrated that CK10 highly activated the "Acute Phase Response Signaling," which results in a wide range of biological activities in response to viral infection, including many inflammatory processes. Further in-depth analysis showed that CK10 exacerbated acute lung injury-associated responses, including inflammatory response, cell death, reactive oxygen species production and complement response. In addition, some of these identified proteins that associated with the lung injury were further confirmed to be regulated in vitro. Therefore, our findings suggest that the early increased lung injury-associated host response induced by CK10 may contribute to the lung pathology and the high virulence of this virus in mice.

HIV Replication Is Not Controlled by CD8+ T Cells during the Acute Phase of the Infection in Humanized Mice.

HIV replication follows a well-defined pattern during the acute phase of the infection in humans. After reaching a peak during the first few weeks after infection, viral replication resolves to a set-point thereafter. There are still uncertainties regarding the contribution of CD8(+) T cells in establishing this set-point. An alternative explanation, supported by in silico modeling, would imply that viral replication is limited by the number of available targets for infection, i.e. CD4(+)CCR5(+) T cells. Here, we used NOD.SCID.gc(-/-) mice bearing human CD4(+)CCR5(+) and CD8(+) T cells derived from CD34(+) progenitors to investigate the relative contribution of both in viral control after the peak. Using low dose of a CCR5-tropic HIV virus, we observed an increase in viral replication followed by "spontaneous" resolution of the peak, similar to humans. To rule out any possible role for CD8(+) T cells in viral control, we infected mice in which CD8(+) T cells had been removed by a depleting antibody. Globally, viral replication was not affected by the absence of CD8(+) T cells. Strikingly, resolution of the viral peak was equally observed in mice with or without CD8(+) T cells, showing that CD8(+) T cells were not involved in viral control in the early phase of the infection. In contrast, a marked and specific loss of CCR5-expressing CD4(+) T cells was observed in the spleen and in the bone marrow, but not in the blood, of infected animals. Our results strongly suggest that viral replication during the acute phase of the infection in humanized mice is mainly constrained by the number of available targets in lymphoid tissues rather than by CD8(+) T cells.

Acute phase response elicited by experimental bovine diarrhea virus (BVDV) infection is associated with decreased vitamin D and E status of vitamin-replete preruminant calves.

Studies in young animals have shown an association between vitamin deficiencies and increased risk of infectious disease; however, there is a paucity of information regarding the effect of acute infection on the vitamin status of the vitamin-replete neonate. To characterize the effects of acute infection on vitamin D and E status of the neonate, 6 vitamin-replete preruminant Holstein bull calves were experimentally infected with bovine viral diarrhea virus (BVDV; strain BVDV2-1373). Six mock-inoculated calves served as controls. Sustained pyrexia, leukopenia, and asynchronous increases in serum haptoglobin and serum amyloid A characterized the response of calves to infection with BVDV. Infection was also associated with increased serum IFN-γ, IL-2, and IL-6 concentrations. During the last 8 d of the 14-d postinoculation period, serum 25-hydroxyvitamin D and α-tocopherol concentrations in infected calves decreased by 51 and 82%, respectively. The observed inverse association between vitamin D and E status and serum amyloid A in infected calves suggests that the infection-induced acute phase response contributed to the reduced vitamin status of these animals. Additional studies are necessary to determine if the negative effect of infection on status are unique to this specific infection model or is representative of preruminant calf's response to acute infection. Studies are also needed to characterize mechanisms underlying infection-related changes in vitamin D and E status and to determine whether additional vitamin D or E supplementation during an acute infection diminishes disease severity and duration in the young animal.

Development and comparative evaluation of SYBR Green I-based one-step real-time RT-PCR assay for detection and quantification of West Nile virus in human patients.

The recent outbreaks of West Nile Virus (WNV) in the Northeastern American continents and other regions of the world have made it essential to develop an efficient protocol for surveillance of WN virus. Nucleic acid based techniques like, RT-PCR have the advantage of sensitivity, specificity and rapidity. A one step single tube Env gene specific real-time RT-PCR was developed for early and reliable clinical diagnosis of WNV infection in clinical samples. The applicability of this assay for clinical diagnosis was validated with 105 suspected acute-phase serum and plasma samples from the recent epidemic of mysterious fever in Tamil Nadu, India in 2009-10. The comparative evaluation revealed the higher sensitivity of real-time RT-PCR assay by picking up 4 additional samples with low copy number of template in comparison to conventional RT-PCR. All the real-time positive samples further confirmed by CDC reported TaqMan real-time RT-PCR and quantitative real-time RT-PCR assays for the simultaneous detection of WNV lineage 1 and 2 strains. The quantitation of the viral load samples was done using a standard curve. These findings demonstrated that the assay has the potential usefulness for clinical diagnosis due to detection and quantification of WNV in acute-phase patient serum samples.

Human antibody responses to avian influenza A(H7N9) virus, 2013.

Understanding host antibody response is crucial for predicting disease severity and for vaccine development. We investigated antibody responses against influenza A(H7N9) virus in 48 serum samples from 21 patients, including paired samples from 15 patients. IgG against subtype H7 and neutralizing antibodies (NAbs) were not detected in acute-phase samples, but ELISA geometric mean titers increased in convalescent-phase samples; NAb titers were 20-80 (geometric mean titer 40). Avidity to IgG against subtype H7 was significantly lower than that against H1 and H3. IgG against H3 was boosted after infection with influenza A(H7N9) virus, and its level in acute-phase samples correlated with that against H7 in convalescent-phase samples. A correlation was also found between hemagglutinin inhibition and NAb titers and between hemagglutinin inhibition and IgG titers against H7. Because of the relatively weak protective antibody response to influenza A(H7N9), multiple vaccinations might be needed to achieve protective immunity.

Decreased mean platelet volume in children with acute rotavirus gastroenteritis.

BACKGROUND: The contribution of platelets to the inflammatory response via several platelet derived mediators is well recognized. The role of mean platelet volume (MPV) in infectious and inflammatory disorders, however, has not yet been well-established. While some of the previous studies demonstrated that MPV acted as a positive acute phase reactant, several others suggested its role as a negative acute phase reactant. In the current study, we aimed to assess the role of MPV as an acute phase reactant in children with rotavirus gastroenteritis. METHODS: We undertook a prospective, randomized, controlled, cross-sectional study and enrolled children diagnosed with acute rotavirus gastroenteritis and healthy controls (HC), between August and November 2012. Children with acute gastroenteritis were assigned either in the rotavirus-positive acute gastroenteritis (RPAG) or in the rotavirus-negative acute gastroenteritis (RNAG) group depending on their stool antigen results. Patients were also classified into two groups based on their Vesikari score (< 11: non-severe and ≥ 11: severe). Complete blood count and C-reactive protein (CRP) levels were assessed for all patients. We compared MPV between RPAG, RNAG and HC groups and investigated the association, if any, among MPV, platelets, white blood count and CRP. RESULTS: In total 100 RPAG (54 males; mean age: 38.74 ± 41.45 months), 100 RNAG (58 males; mean age: 32.84 ± 29.64 months) children and 100 HC (43 males; mean age: 33.21 ± 32.55 months) were enrolled into the study. Mean platelet counts were well-matched among groups (p > 0.05). We observed a steady decline in MPV (fL) in the HC, RPAG and RNAG groups (median 7.80, 7.35 and 7.30, respectively; p < 0.0001). We did not find an association between MPV and the clinical score of gastroenteritis (p > 0.05). CONCLUSION: We found that MPV could be used as an acute phase reactant in children with rotavirus gastroenteritis. We believe that the current study will contribute to our understanding of MPV as an inflammatory marker.

Comparative study of clinical courses, gross lesions, acute phase response and coagulation disorders in sheep inoculated with bluetongue virus serotype 1 and 8.

Bluetongue virus serotypes 1 (BTV-1) and 8 (BTV-8) have been described as the most prevalent in Europe during recent outbreaks displaying intense virulence, sheep being among the most severely affected livestock species. However, BTV pathogenesis is still unclear. This study sought to elucidate differences in the pathogenetic mechanisms of BTV-1 and -8 in sheep. For this purpose, a time-course study was carried out, with sequential sacrifices in order to relate pathological lesions to changes in a range of virological and serological parameters. A greater virulence of BTV-1 was probed. BTV-1 infected sheep showed a longer clinical course, with a significant increase of clinical signs and more severe gross lesions than BTV-8 infected sheep. These differences appear not to be attributable to greater virus replication, suggesting viral loads did not influence in the pathogenicity of these serotypes. While both groups displayed an early, intense antibody response, they still developed clinical signs and lesions characteristic of bluetongue, indicating a lack of correlation between antibody levels and protection against the disease. Both acute phase response (APR) and thrombocytopenia induced by BTV-1 in sheep were more intense. Furthermore, an association between acute phase proteins (APPs) concentrations and the evolution of clinical signs and gross lesions was also observed, suggesting the existence of a direct link between the pathogenicity of BTV serotypes, the severity of vascular lesions and the serum concentrations of APPs. To our knowledge, this is the first verification of a measurable APR in sheep with both experimental and naturally occurring bluetongue.

Platelet ligands and ADAMTS13 during Puumala hantavirus infection and associated thrombocytopenia.

We aimed here to elucidate the role of adhesive platelet ligands and endothelial involvement during the acute phase of Puumala hantavirus (PUUV) infection. Nineteen hospital-treated patients with serologically confirmed diagnosis of acute PUUV infection were included. Patient charts were reviewed for clinical and basic laboratory data. Plasma levels of von Willebrand factor antigen (VWF:Ag), ristocetin cofactor (VWF:RCo), factor VIII (FVIII:C) and a disintegrin and metalloproteinase with a thrombospondin type 1 domain 13 (ADAMTS13) activities as well as fibrinogen and fibronectin were measured three times acutely and once during the recovery phase. VWF:Ag and VWF:RCo were nearly three-fold higher acutely compared with recovery (median 252 vs. 88%, and mean 267 vs. 98%, respectively; P<0.001 for both), whereas FVIII:C was only slightly elevated (median 118 vs. 88%, P=0.002) and remarkably failed to show association with VWF in the acute phase. ADAMTS13 activity and fibronectin concentration were lower in the acute compared with the recovery phase (median 56 vs. 63%, P=0.003, and median 221 vs. 330 µmol/l, P=0.001, respectively). Fibrinogen raised acutely (mean 5.0 vs. 3.3 g/l, P<0.001), negatively correlating with the platelet count (r=-0.468, P=0.043). Markedly upregulated fibrinogen and VWF together with decreased levels of ADAMTS13 activity and fibronectin were observed during acute PUUV infection. VWF and FVIII:C did not associate during the acute phase, whereas thrombocytopenia correlated negatively with fibrinogen. These findings imply several rearranged interactions between platelets and their ligands.

TLR-mediated up-regulation of serum retroviral gp70 is controlled by the Sgp loci of lupus-prone mice.

The endogenous retroviral envelope glycoprotein, gp70, implicated in murine systemic lupus erythematosus (SLE), has been considered to be a product of xenotropic, polytropic (PT) and modified PT (mPT) endogenous retroviruses. It is secreted by hepatocytes like an acute phase protein, but its response is under a genetic control. Given critical roles of TLR7 and TLR9 in the pathogenesis of SLE, we assessed their contribution to the acute phase expression of serum gp70, and defined a pivotal role of the Sgp3 (serum gp70 production 3) and Sgp4 loci in this response. Our results demonstrated that serum levels of gp70 were up-regulated in lupus-prone NZB mice injected with TLR7 or TLR9 agonist at levels comparable to those induced by injection of IL-1, IL-6 or TNF. In addition, studies of C57BL/6 Sgp3 and/or Sgp4 congenic mice defined the major roles of these two loci in up-regulated production of serum gp70 during acute phase responses. Finally, the analysis of Sgp3 congenic mice strongly suggests the presence of at least two distinct genetic factors in the Sgp3 interval, one of which controlled the basal-level expression of xenotropic, PT and mPT gp70 and the other which controlled the up-regulated production of xenotropic and mPT gp70 during acute phase responses. Our results uncovered an additional pathogenic role of TLR7 and TLR9 in murine lupus nephritis by promoting the expression of nephritogenic gp70 autoantigen. Furthermore, they revealed the involvement of multiple regulatory genes for the expression of gp70 autoantigen under steady-state and inflammatory conditions in lupus-prone mice.

Galectin-9/TIM-3 interaction regulates virus-specific primary and memory CD8 T cell response.

In this communication, we demonstrate that galectin (Gal)-9 acts to constrain CD8(+) T cell immunity to Herpes Simplex Virus (HSV) infection. In support of this, we show that animals unable to produce Gal-9, because of gene knockout, develop acute and memory responses to HSV that are of greater magnitude and better quality than those that occur in normal infected animals. Interestingly, infusion of normal infected mice with alpha-lactose, the sugar that binds to the carbohydrate-binding domain of Gal-9 limiting its engagement of T cell immunoglobulin and mucin (TIM-3) receptors, also caused a more elevated and higher quality CD8(+) T cell response to HSV particularly in the acute phase. Such sugar treated infected mice also had expanded populations of effector as well as memory CD8(+) T cells. The increased effector T cell responses led to significantly more efficient virus control. The mechanisms responsible for the outcome of the Gal-9/TIM-3 interaction in normal infected mice involved direct inhibitory effects on TIM-3(+) CD8(+) T effector cells as well as the promotion of Foxp3(+) regulatory T cell activity. Our results indicate that manipulating galectin signals, as can be achieved using appropriate sugars, may represent a convenient and inexpensive approach to enhance acute and memory responses to a virus infection.

Suppression of IFN-gamma production in atopic group at the acute phase of RSV infection.

Several studies have suggested that respiratory syncytial virus (RSV) bronchiolitis induced the change of cytokine production profile in childhood. We sought to determine whether the RSV-induced cytokine production was affected by the patient's atopic background. We quantified interferon-gamma (IFN-gamma) and interleukin (IL)-4 in the supernatant of peripheral blood mononuclear cells (PBMCs) cultured for 24 h and in the presence of phytohemaglutinin (PHA), IL-12, or IL-18, from 14 infants who were divided into two groups, those who are non-atopic and an atopic group. In RSV-infected infants with atopic diseases, IFN-gamma production from IL-12- or especially IL-18-stimulated PBMCs was subtotally suppressed in the acute phase, whereas in RSV-infected infants without atopic diseases IFN-gamma production was not suppressed on acute phase. The IFN-gamma suppression observed in the atopic group is not caused by the immaturity of an infant's immune system since reduced IFN-gamma production to RSV is not observed in the infants of non-atopic group. IFN-gamma suppression in regard to RSV infection might be caused by some genetic factor involved in the development of atopic disease such as IL-18 signal cascade.

[Does the assay of acute phase protein concentrations in cerebrospinal fluid and/or in serum in patient with viral meningitis have a diagnostic value? Part II. Lymphocytic meningitis caused by echo 30 virus]. / Czy oznaczanie stezen bialek ostrej fazy w plynie mózgowo-rdzeniowym lub/i w surowicy w wirusowym zapaleniu opon mózgowo-rdzeniowych u dzieci ma znaczenie diagnostyczne? Czessc II. Limfocytarne zapalenie opon mózgowo-rdzeniowych wywolane wirusem ECHO 30.

The aim of the study was to evaluate dynamics of selected acute phase proteins in serum and cerebrospinal fluid (CSF) in children with viral meningitis and to assess diagnostic power of protein determination for detection and treatment monitoring. 51 children with viral meningitis caused by ECHO 30 virus were included in the study group. Concentration of C-reactive protein (CRP), alpha 1-antitrypsin (AAT), alpha1-acid glycoprotein (AAG), alpha2-haptoglobin (HPT) and C3 complement fragment were determined in serum and CSF at entry and at day 14 after admittance to hospital. Control group for serum determination consisted in 30 healthy children (Group K1) and control group for CSF determination consisted in 19 hospitalized children in whom the diagnosis of meningitis was not confirmed (group K2). The greatest rise of acute phase proteins concentration was observed in children in case of HPT, AAG and C3 complement when determined in serum. Meningitis in children that was caused by ECHO 30 virus produces slight acute phase reaction that is more evident in serum than in CSF. It is confirmed by remarkable increase of AAG, HPT, C3 complement in serum and HPT in CSF either at entry or at the day 14. The determination of AAG, HPT and C3 complement in serum have diagnostic power that is strong enough to meningitis diagnostics and monitoring of treatment.

Metallothionein is induced and trace element balance changed in target organs of a common viral infection.

In experimental studies on the common human coxsackievirus B type 3 (CB3) infection, administered cadmium (Cd) is known to accumulate in the liver and kidneys. CB3 adapted to Balb/c mice was used to study whether infection affects the Cd-binding protein, metallothionein (MT) and if this alters the normal physiological trace element balance in the liver, kidney, spleen and brain. On day 3 of infection, degradation of liver proteins (44%, P<0.01) occurred, whereas in the spleen, protein increased (63%, P<0.05). The infection increased MT five-fold (P<0.01) in liver and kidneys, and in spleen by 34% (P<0.05). A redistribution of Cd and copper (Cu) from the liver to the kidney was associated with this increase in MT, resulting in an increased (P<0.01) kidney/liver ratio for both elements. The infection increased the zinc (Zn) concentration more in the kidney than in the liver, but the kidney/liver ratio was not significantly affected. Results show that MT is increased in several organs during the early phase of infection and is associated with redistribution of both essential and non-essential trace elements. This may be a normal response in common infections that could adversely influence the pathogenesis when the host is concomitantly exposed to potentially toxic trace elements, even at levels in the physiological range.

Neurologic morbidity after herpes simplex virus type 2 meningitis: a retrospective study of 40 patients.

In order to study the long-term course after herpes simplex virus type 2 (HSV-2) meningitis and/or myeloradiculitis the records of 40 consecutive patients were studied. During the year following the acute phase, verified or suspected neurologic recurrences were noted in nearly half of the patients: 1 or more episodes of recurring meningitis were noted in 8 patients; new episodes of myelitis or radiculitis in 3; distinct attacks of headache in 4; and diffuse neurologic complaints impairing daily life in 3. Recurring mucocutaneous symptoms were observed in 16 patients. Eleven patients experienced concurrent or separate episodes of recurring mucocutaneous and neurologic symptoms, 7 had neurologic recurrences only and 5 had only mucocutaneous recurrences. As considerable morbidity may result, patients with HSV-2 meningitis and/or myeloradiculitis should be identified by means of thorough history-taking, careful examination and a specific viral diagnosis in order to enable adequate advice and counseling to be provided and to aid decision-making regarding antiviral therapy.

[Does the estimation of acute phase protein concentrations in cerebrospinal fluid and/or in serum in patients with viral meningitis carry diagnostic importance? Part I. Lymphocytic meningitis caused by epidemic parotitis]. / Czy oznaczanie stezen bialek ostrej fazy w plynie mózgowo-rdzeniowym lub/i w surowicy w wirusowym zapaleniu opon mózgowo-rdzeniowych u dzieci ma znaczenie diagnostyczne? Czesc I. Limfocytarne zapalenie opon mózgowo-rdzeniowych wywolane wirusem nagminnego zapalenia przyusznic.

OBJECTIVE: We examined whether an acute phase reaction could occur in children with lymphocytic meningitis of homogeneous etiology (parotitis epidemic from the Paramyxoviridae family), a sign of which would be an increase in concentrations of acute phase proteins (APP's) in cerebrospinal fluid (CSF) and/or in blood serum. We also tested the usefulness of the determination of selected APP's concentrations in CSF and serum in diagnosis and monitoring of the course of the disease, provided that an increase in concentrations of selected APP's were discernible. METHODS: Cases were 78 children with lymphocytic meningitis as a complication of parotitis epidemic. Controls were 30 healthy children (control group K1) and 19 children hospitalized with suspected meningitis (control group K2). The following APP's presence in CSF and serum were tested: C-reactive protein (CRP), alpha-2-haptoglobin (HPT), alpha-1-antitripsin (AAT) and alpha-1-acid glycoprotein (AAG), alpha-2-ceruloplasmin (CER) and alpha-2-macroglobulin (AMG). The results were compared and analyzed. RESULTS: The results of the research show a significant increase in all APP's determined, except for CRP and AAG, in children with parotidal meningitis. CONCLUSIONS: Determination of CRP concentration either in CSF or in serum is not useful in diagnosis of parotidal meningitis and in differentiation of lymphocytic and bacterial forms of the disease.

High-density lipoprotein loses its anti-inflammatory properties during acute influenza a infection.

BACKGROUND: Viruses have been identified as one of a variety of potential agents that are implicated in atherogenesis. METHODS AND RESULTS: C57BL/6J mice were killed before or 2, 3, 5, 7, or 9 days after intranasal infection with 10(5) plaque-forming units (pfu) of Influenza A strain WSN/33. Peak infectivity in lungs was reached by 72 hours, and it returned to baseline by 9 days. No viremia was observed at any time. The activities of paraoxonase and platelet-activating factor acetylhydrolase in HDL decreased after infection and reached their lowest levels 7 days after inoculation. The ability of HDL from infected mice to inhibit LDL oxidation and LDL-induced monocyte chemotactic activity in human artery wall cell cocultures decreased with time after inoculation. Moreover, as the infection progressed, LDL more readily induced monocyte chemotaxis. Peak interleukin-6 and serum amyloid A plasma levels were observed at 2 and 7 days after inoculation. HDL apoA-I levels did not change. ApoJ and ceruloplasmin levels in HDL peaked 3 days after infection. Ceruloplasmin remained elevated throughout the time course, whereas apoJ levels decreased toward baseline after the third day. CONCLUSIONS: We conclude that alterations in the relative levels of paraoxonase, platelet-activating factor acetylhydrolase, ceruloplasmin, and apoJ in HDL occur during acute influenza infection, causing HDL to lose its anti-inflammatory properties.

Viral etiology of intussusception in Taiwanese childhood.

BACKGROUND: Adenovirus infection and lymphoid hyperplasia have been associated with childhood intussusception. However, the extent of other viruses involved in this condition remains unclear. This prospective study investigates the relationship between some lymphotropic viruses and current childhood intussusception. METHODS: Patients with intussusception encountered in a pediatric emergency department in a recent 3-year period were studied. Healthy infants and toddlers of comparable age served as controls. Throat and rectal viral cultures were performed in patients and controls. Viral antibodies against adenovirus, cytomegalovirus, human herpesvirus (HHV)-6, HHV-7 and Epstein-Barr virus (EBV) were tested in paired sera from the patients. Acute stage serum from each patient and mesenteric lymph nodes from patients requiring surgery were studied for the presence of adenovirus genome by PCR. RESULTS: Twenty-seven of 61 (44.3%) intussusception patients, but only 2 of 52 (3.8%) healthy controls shed nonenteric adenovirus in throat and rectal specimens (P < 0.001). Of the 27 (74.1%) patients who shed adenovirus, 20 were older than 1 year old, whereas only 1 of 15 (6.7%) similarly aged patients in a previous study from the same area three decades ago did so (P = 0.001). Among 43 patients with available paired sera, acute primary viral infection was found in 17 (39.5%) by adenovirus, 4 (9.3%) by HHV-6, 5 (11.6%) by HHV-7, 2 (4.7%) by EBV and none by cytomegalovirus. Multiple viral infections occurred in 6 patients. Adenovirus genome was detected in 4 of 9 mesenteric lymph nodes and in only 3 of 60 (5%) acute phase sera. CONCLUSIONS: Primary nonenteric adenovirus infection contributes to current childhood intussusception. Acute primary HHV-6, HHV-7 and EBV infections also play etiologic roles.

Influenza A virus infection increases IgE production and airway responsiveness in aerosolized antigen-exposed mice.

BACKGROUND: Respiratory viral infection is known clinically to promote sensitization to antigen inhalation and the development of asthma. OBJECTIVE: The purpose of this investigation was to determine whether influenza type A virus infection enhances inhalation sensitization and increases airway responsiveness in mice. METHODS: Mice were infected by intranasal inoculation with influenza A viruses (strains: H1N1 and H3N2) or PBS. Animals were exposed to aerosols of ovalbumin on day 3. Two weeks after ovalbumin sensitization, mice were challenged with ovalbumin aerosols; 24 hours later, airway responsiveness (AR) to inhaled methacholine, levels of ovalbumin-specific IgE, and bronchoalveolar lavage fluid (BALF) were examined. RESULTS: Neither influenza A virus (H1N1 nor H3N2) alone nor ovalbumin sensitization alone caused changes in AR or IgE. However, ovalbumin sensitization after inoculation with either influenza A virus increased AR and levels of ovalbumin-specific IgE. On BALF-cell analysis, ovalbumin sensitization after inoculation with influenza virus A increased the number of lymphocytes but not the number of eosinophils. No difference in AR or IgE levels was observed between the 2 strains of influenza A viruses. Immmunostaining of BALF cells showed an increase in T cells, especially CD8(+) cells, with ovalbumin sensitization after inoculation with influenza virus A. CONCLUSION: Infection by influenza A virus enhances sensitization to inhaled antigens and airway responsiveness in mice by means of mechanisms including CD8(+) cells and antigen-specific IgE.