Last data update: Jun 17, 2024. (Total: 47034 publications since 2009)
Records 1-14 (of 14 Records) |
Query Trace: De La Cruz JA [original query] |
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Highly pathogenic avian influenza A(H5N1) virus infection in a dairy farm worker
Uyeki TM , Milton S , Abdul Hamid C , Reinoso Webb C , Presley SM , Shetty V , Rollo SN , Martinez DL , Rai S , Gonzales ER , Kniss KL , Jang Y , Frederick JC , De La Cruz JA , Liddell J , Di H , Kirby MK , Barnes JR , Davis CT . N Engl J Med 2024 ![]() ![]() |
Quinazolin-derived myeloperoxidase inhibitor suppresses influenza A virus-induced reactive oxygen species, pro-inflammatory mediators and improves cell survival
De La Cruz JA , Ganesh T , Diebold BA , Cao W , Hofstetter A , Singh N , Kumar A , McCoy J , Ranjan P , Smith SME , Sambhara S , Lambeth JD , Gangappa S . PLoS One 2021 16 (7) e0254632 Superoxide radicals and other reactive oxygen species (ROS) are implicated in influenza A virus-induced inflammation. In this in vitro study, we evaluated the effects of TG6-44, a novel quinazolin-derived myeloperoxidase-specific ROS inhibitor, on influenza A virus (A/X31) infection using THP-1 lung monocytic cells and freshly isolated peripheral blood mononuclear cells (PBMC). TG6-44 significantly decreased A/X31-induced ROS and virus-induced inflammatory mediators in THP-1 cells (IL-6, IFN-γ, MCP-1, TNF-α, MIP-1β) and in human PBMC (IL-6, IL-8, TNF-α, MCP-1). Interestingly, TG6-44-treated THP-1 cells showed a decrease in percent cells expressing viral nucleoprotein, as well as a delay in translocation of viral nucleoprotein into the nucleus. Furthermore, in influenza A virus-infected cells, TG6-44 treatment led to suppression of virus-induced cell death as evidenced by decreased caspase-3 activation, decreased proportion of Annexin V+PI+ cells, and increased Bcl-2 phosphorylation. Taken together, our results demonstrate the anti-inflammatory and anti-infective effects of TG6-44. |
Cluster of Oseltamivir-Resistant and Hemagglutinin Antigenically Drifted Influenza A(H1N1)pdm09 Viruses, Texas, USA, January 2020
Mohan T , Nguyen HT , Kniss K , Mishin VP , Merced-Morales AA , Laplante J , St George K , Blevins P , Chesnokov A , De La Cruz JA , Kondor R , Wentworth DE , Gubareva LV . Emerg Infect Dis 2021 27 (7) 1953-1957 Four cases of oseltamivir-resistant influenza A(H1N1)pdm09 virus infection were detected among inhabitants of a border detention center in Texas, USA. Hemagglutinin of these viruses belongs to 6B.1A5A-156K subclade, which may enable viral escape from preexisting immunity. Our finding highlights the necessity to monitor both drug resistance and antigenic drift of circulating viruses. |
Susceptibility of widely diverse influenza a viruses to PB2 polymerase inhibitor pimodivir.
Patel MC , Chesnokov A , Jones J , Mishin VP , De La Cruz JA , Nguyen HT , Zanders N , Wentworth DE , Davis TC , Gubareva LV . Antiviral Res 2021 188 105035 ![]() ![]() Pimodivir exerts an antiviral effect on the early stages of influenza A virus replication by inhibiting the cap-binding function of polymerase basic protein 2 (PB2). In this study, we used a combination of sequence analysis and phenotypic methods to evaluate pimodivir susceptibility of influenza A viruses collected from humans and other hosts. Screening PB2 sequences for substitutions previously associated with reduced pimodivir susceptibility revealed a very low frequency among seasonal viruses circulating in the U.S. during 2015-2020 (<0.01%; 3/11,934) and among non-seasonal viruses collected in various countries during the same period (0.2%; 18/8971). Pimodivir potently inhibited virus replication in two assays, a single-cycle HINT and a multi-cycle FRA, with IC(50) values in a nanomolar range. Median IC(50) values determined by HINT were similar for both subtypes of seasonal viruses, A (H1N1)pdm09 and A (H3N2), across three seasons. Human seasonal viruses with PB2 substitutions S324C, S324R, or N510K displayed a 27-317-fold reduced pimodivir susceptibility. In addition, pimodivir was effective at inhibiting replication of a diverse group of animal-origin viruses that have pandemic potential, including avian viruses of A (H5N6) and A (H7N9) subtypes. A rare PB2 substitution H357N was identified in an A (H4N2) subtype poultry virus that displayed >100-fold reduced pimodivir susceptibility. Our findings demonstrate a broad inhibitory activity of pimodivir and expand the existing knowledge of amino acid substitutions that can reduce susceptibility to this investigational antiviral. |
Detection of baloxavir resistant influenza A viruses using next generation sequencing and pyrosequencing methods.
Patel MC , Mishin VP , De La Cruz JA , Chesnokov A , Nguyen HT , Wilson MM , Barnes J , Kondor RJG , Wentworth DE , Gubareva LV . Antiviral Res 2020 182 104906 ![]() Baloxavir, a new antiviral drug targeting cap-dependent endonuclease activity of polymerase acidic (PA) protein of influenza viruses, is now approved in multiple countries. Several substitutions at isoleucine 38 in PA protein (e.g., PA-I38T) have been associated with decreased baloxavir susceptibility in vitro and in vivo. In recent years, next generation sequencing (NGS) analysis and pyrosequencing have been used by CDC and U.S. Public Health Laboratories to monitor drug susceptibility of influenza viruses. Here we described an improved pyrosequencing assay for detecting influenza A viruses carrying substitutions at PA-38. Cyclic and customized orders of nucleotide dispensation were evaluated, and pyrosequencing results were compared to those generated using NGS. Our data showed that the customized nucleotide dispensation has improved the pyrosequencing assay performance in identification of double mixtures (e.g., PA-38I/T); however, identification of PA-38 variants in triple mixtures remains a challenge. While NGS analysis indicated the presence of PA-I38K in one clinical specimen and isolate, our attempts to detect this mutation by pyrosequencing or recover the virus carrying PA-I38K in cell culture were unsuccessful, raising a possibility of a rarely occurring sequencing error. Overall, pyrosequencing provides a convenient means to detect baloxavir resistant influenza viruses when NGS is unavailable or a faster turnaround time is required. |
Replicative fitness of seasonal influenza A viruses with decreased susceptibility to baloxavir
Chesnokov A , Patel MC , Mishin VP , De La Cruz JA , Lollis L , Nguyen HT , Dugan V , Wentworth DE , Gubareva LV . J Infect Dis 2019 221 (3) 367-371 Susceptibility of influenza A viruses to baloxavir can be affected by changes at amino acid residue 38 in polymerase acidic (PA) protein. Information on replicative fitness of PA-I38-substituted viruses remains sparse. We demonstrated that substitutions I38L/M/S/T not only had a differential effect on baloxavir susceptibility (9- to 116-fold), but also on in vitro replicative fitness. While I38L conferred undiminished growth, other substitutions led to mild attenuation. In a ferret model, control viruses outcompeted those carrying I38M or I38T substitutions, although their advantage was limited. These findings offer insights into the attributes of baloxavir resistant viruses needed for informed risk assessment. |
Avian influenza A(H7N2) virus in human exposed to sick cats, New York, USA, 2016
Marinova-Petkova A , Laplante J , Jang Y , Lynch B , Zanders N , Rodriguez M , Jones J , Thor S , Hodges E , De La Cruz JA , Belser J , Yang H , Carney P , Shu B , Berman L , Stark T , Barnes J , Havers F , Yang P , Trock SC , Fry A , Gubareva L , Bresee JS , Stevens J , Daskalakis D , Liu D , Lee CT , Torchetti MK , Newbury S , Cigel F , Toohey-Kurth K , St George K , Wentworth DE , Lindstrom S , Davis CT . Emerg Infect Dis 2017 23 (12) 2046-9 An outbreak of influenza A(H7N2) virus in cats in a shelter in New York, NY, USA, resulted in zoonotic transmission. Virus isolated from the infected human was closely related to virus isolated from a cat; both were related to low pathogenicity avian influenza A(H7N2) viruses detected in the United States during the early 2000s. |
An oil-in-water nanoemulsion enhances immunogenicity of H5N1 vaccine in mice
Cao W , Davis WG , Kim JH , De La Cruz JA , Taylor A , Hendrickson GR , Kumar A , Ranjan P , Lyon LA , Katz JM , Gangappa S , Sambhara S . Nanomedicine 2016 12 (7) 1909-1917 To enhance the immunogenicity of the Influenza H5N1 vaccine, we developed an oil-in-water nanoemulsion (NE) adjuvant. NE displayed good temperature stability and maintained particle size. More importantly, it significantly enhanced IL-6 and MCP-1 production to recruit innate cells, including neutrophils, monocytes/macrophages and dendritic cells to the local environment. Furthermore, NE enhanced dendritic cell function to induce robust antigen-specific T and B cell immune responses. NE-adjuvanted H5N1 vaccine not only elicited significantly higher and long-lasting antibody responses, but also conferred enhanced protection against homologous clade 1 as well as heterologous clade 2 H5N1 virus challenge in young as well as in aged mice. The pre-existing immunity to seasonal influenza did not affect the immunogenicity of NE-adjuvanted H5N1 vaccine. |
NADPH oxidase 1 is associated with altered host survival and t cell phenotypes after influenza A virus infection in mice
Hofstetter AR , De La Cruz JA , Cao W , Patel J , Belser JA , McCoy J , Liepkalns JS , Amoah S , Cheng G , Ranjan P , Diebold BA , Shieh WJ , Zaki S , Katz JM , Sambhara S , Lambeth JD , Gangappa S . PLoS One 2016 11 (2) e0149864 The role of the reactive oxygen species-producing NADPH oxidase family of enzymes in the pathology of influenza A virus infection remains enigmatic. Previous reports implicated NADPH oxidase 2 in influenza A virus-induced inflammation. In contrast, NADPH oxidase 1 (Nox1) was reported to decrease inflammation in mice within 7 days post-influenza A virus infection. However, the effect of NADPH oxidase 1 on lethality and adaptive immunity after influenza A virus challenge has not been explored. Here we report improved survival and decreased morbidity in mice with catalytically inactive NADPH oxidase 1 (Nox1*/Y) compared with controls after challenge with A/PR/8/34 influenza A virus. While changes in lung inflammation were not obvious between Nox1*/Y and control mice, we observed alterations in the T cell response to influenza A virus by day 15 post-infection, including increased interleukin-7 receptor-expressing virus-specific CD8+ T cells in lungs and draining lymph nodes of Nox1*/Y, and increased cytokine-producing T cells in lungs and spleen. Furthermore, a greater percentage of conventional and interstitial dendritic cells from Nox1*/Y draining lymph nodes expressed the co-stimulatory ligand CD40 within 6 days post-infection. Results indicate that NADPH oxidase 1 modulates the innate and adaptive cellular immune response to influenza virus infection, while also playing a role in host survival. Results suggest that NADPH oxidase 1 inhibitors may be beneficial as adjunct therapeutics during acute influenza infection. |
A Newly Emerged Swine-Origin Influenza A(H3N2) Variant Dampens Host Antiviral Immunity but Induces Potent Inflammasome Activation
Cao W , Mishina M , Ranjan P , De La Cruz JA , Kim JH , Garten R , Kumar A , Garcia-Sastre A , Katz JM , Gangappa S , Sambhara S . J Infect Dis 2015 212 (12) 1923-9 We compared the innate immune response to newly emerged swine origin H3N2 influenza A variant virus containing the M gene from A(H1N1)pdm09 virus (A(H3N2)vpm), with 2010 swine-origin A(H3N2)v and seasonal A(H3N2) viruses. Our results demonstrated that A(H3N2)vpM virus-induced myeloid dendritic cells secreted significantly lower levels of type I interferon (IFN) but produced significantly higher levels of pro-inflammatory cytokines and induced potent inflammasome activation. The reduction in antiviral immunity with increased inflammatory responses upon A(H3N2)vpM virus infection suggest that these viruses have the potential for increased disease severity in susceptible hosts. |
Neuraminidase mutations conferring resistance to oseltamivir in influenza A(H7N9) viruses
Marjuki H , Mishin VP , Chesnokov AP , De La Cruz JA , Davis CT , Villanueva JM , Fry AM , Gubareva LV . J Virol 2015 89 (10) 5419-26 Human infections by avian influenza A(H7N9) virus entail substantial morbidity and mortality. Treatment of infected patients with the neuraminidase (NA) inhibitor oseltamivir was associated with emergence of viruses carrying NA substitutions. In the NA inhibition (NI) assay, R292K conferred highly reduced inhibition by oseltamivir, while E119V and I222K each caused reduced inhibition. To facilitate establishment of laboratory correlates of clinically relevant resistance, experiments were conducted in ferrets infected with virus carrying wild-type or variant NA genes recovered from the A/Taiwan/1/2013 isolate. Oseltamivir treatment (5 or 25 mg/kg/dose) was given 4 hours post-infection followed by twice daily treatment for 5 days. Treatment of ferrets infected with wild-type virus resulted in a modest dose-dependent reduction (0.7-1.5 log10TCID50) in nasal wash viral titers and inflammation response. Conversely, treatment failed to significantly inhibit the replication of R292K or E119V viruses. A small reduction of viral titers was detected on day 5 in ferrets infected with the I222K virus. Propensity for oseltamivir resistance emergence was assessed in oseltamivir-treated animals infected with wild-type virus; emergence of R292K virus was detected in 3 of 6 ferrets within 5-7 days post-infection. Collectively, we demonstrate that R292K, E119V and I222K reduced the inhibitory activity of oseltamivir not only in the NI assay, but also in infected ferrets, judged particularly by viral loads in nasal washes, and may signal the need for alternative therapeutics. Thus, these clinical outcomes measured in the ferret model may correlate with clinically relevant oseltamivir resistance in humans. IMPORTANCE: This report provides more evidence for using the ferret model to assess susceptibility of influenza A(H7N9) viruses to oseltamivir, the most prescribed anti-influenza drug. The information gained can be used to assist in the establishment of laboratory correlates of human disease and drug therapy. The rapid emergence of viruses with R292K in treated ferrets correlates well with the multiple reports on this NA variant in treated human patients. Our findings highlight the importance for discovery and characterization of new antiviral drugs with different mechanism of action and the use of combination treatment strategies against emerging viruses with pandemic potential such as avian H7N9 virus, particularly against those carrying drug resistance markers. |
Characterization of drug-resistant influenza A(H7N9) variant viruses isolated from an oseltamivir-treated patient in Taiwan
Marjuki H , Mishin VP , Chesnokov AP , Jones J , De La Cruz JA , Sleeman K , Tamura D , Nguyen HT , Wu HS , Chang FY , Liu MT , Fry AM , Cox NJ , Villanueva JM , Davis CT , Gubareva LV . J Infect Dis 2014 211 (2) 249-57 BACKGROUND: Patients contracting influenza A(H7N9) often developed severe disease causing respiratory failure. Neuraminidase (NA) inhibitors (NAIs) are the primary option for treatment, but information on drug-resistance markers for A(H7N9) is limited. METHODS: Four NA variants of A/Taiwan/1/2013 (H7N9) virus containing a single substitution (NA-E119 V, NA-I222 K, NA-I222R or NA-R292 K), recovered from an oseltamivir-treated patient, were tested for NAI susceptibility in vitro; their replicative fitness was evaluated in cell culture, mice and ferrets. RESULTS: NA-R292 K led to highly reduced inhibition by oseltamivir and peramivir, while NA-E119 V, NA-I222 K and NA-I222R caused reduced inhibition by oseltamivir. Mice infected with any virus showed severe clinical signs with high mortality rates. NA-I222 K virus was the most virulent in mice, whereas virus lacking NA change (NA-WT) and NA-R292 K virus seemed the least virulent. Sequence analysis suggests that PB2-S714N increased virulence of the NA-I222 K virus in mice; NS1-K126R, alone or in combination with PB2-V227M, produced contrasting effects in NA-WT and NA-R292 K viruses. In ferrets, all viruses replicated to high titers in the upper respiratory tract, but produced only mild illness. NA-R292 K virus, showed reduced replicative fitness in this animal model. CONCLUSIONS: Our data highlight challenges in assessment of replicative fitness of H7N9 NA variants emerged in NAI-treated patients. |
An investigational antiviral drug, DAS181, effectively inhibits replication of zoonotic influenza A virus subtype H7N9 and protects mice from lethality
Marjuki H , Mishin VP , Chesnokov AP , De La Cruz JA , Fry AM , Villanueva J , Gubareva LV . J Infect Dis 2014 210 (3) 435-40 Human infections caused by the avian influenza A(H7N9) virus have been associated with substantial morbidity and mortality. Emergence of virus variants, carrying markers of decreased susceptibility to neuraminidase inhibitors, was reported. Here we showed that fludase, an antiviral drug with sialidase activity, potently inhibited replication of wild-type H7N9 viruses and their oseltamivir-resistant R292 K variants in mice. A once-daily administration initiated early after lethal infection, hampered body weight loss and completely protected mice from lethality. We observed a time-dependent effect for 24-72-hour delayed fludase treatments on morbidity and mortality. The results warrant further investigation of fludase for influenza treatment. |
Rapid differentiation of monocytes into type I IFN-producing myeloid dendritic cells as an antiviral strategy against influenza virus infection
Cao W , Taylor AK , Biber RE , Davis WG , Kim JH , Reber AJ , Chirkova T , De La Cruz JA , Pandey A , Ranjan P , Katz JM , Gangappa S , Sambhara S . J Immunol 2012 189 (5) 2257-65 ![]() Myeloid dendritic cells (mDCs) have long been thought to function as classical APCs for T cell responses. However, we demonstrate that influenza viruses induce rapid differentiation of human monocytes into mDCs. Unlike the classic mDCs, the virus-induced mDCs failed to upregulate DC maturation markers and were unable to induce allogeneic lymphoproliferation. Virus-induced mDCs secreted little, if any, proinflammatory cytokines; however, they secreted a substantial amount of chemoattractants for monocytes (MCP-1 and IP-10). Interestingly, the differentiated mDCs secreted type I IFN and upregulated the expression of IFN-stimulated genes (tetherin, IFITM3, and viperin), as well as cytosolic viral RNA sensors (RIG-I and MDA5). Additionally, culture supernatants from virus-induced mDCs suppressed the replication of virus in vitro. Furthermore, depletion of monocytes in a mouse model of influenza infection caused significant reduction of lung mDC numbers, as well as type I IFN production in the lung. Consequently, increased lung virus titer and higher mortality were observed. Taken together, our results demonstrate that the host responds to influenza virus infection by initiating rapid differentiation of circulating monocytes into IFN-producing mDCs, which contribute to innate antiviral immune responses. |
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