Murine Model for the Study of Influenza D Virus

ABSTRACT A novel genus within the Orthomyxoviridae family was identified in the United States and named influenza D virus (IDV). Bovines have been proposed to be the primary host, and three main viral lineages (D/OK-like, D/660-like, and D/Japan-like) have been described. Experimental infections had previously been performed in swine, ferrets, calves, and guinea pigs in order to study IDV pathogenesis. We developed a murine experimental model to facilitate the study of IDV pathogenesis and the immune response. DBA/2 mice were inoculated with 105 50% tissue culture infective dose (TCID50) of D/bovine/France/5920/2014 (D/OK-like). No clinical signs or weight loss were observed. Viral replication was observed mainly in the upper respiratory tract (nasal turbinates) but also in the lower respiratory tract of infected mice, with a peak at 4 days postinfection. Moreover, the virus was also detected in the intestines. All infected mice seroconverted by 14 days postinfection. Transcriptomic analyses demonstrated that IDV induced the activation of proinflammatory genes, such as gamma interferon (IFN-γ) and CCL2. Inoculation of NF-κB-luciferase and Ifnar1−/− mice demonstrated that IDV induced mild inflammation and that a type I interferon response was not necessary in IDV clearance. Adaptation of IDV by serial passages in mice was not sufficient to induce disease or increased pathogenesis. Taken together, present data and comparisons with the calf model show that our mouse model allows for the study of IDV replication and fitness (before selected viruses may be inoculated on calves) and also of the immune response. IMPORTANCE Influenza D virus (IDV), a new genus of Orthomyxoviridae family, presents a large host range and a worldwide circulation. The pathogenicity of this virus has been studied in the calf model. The mouse model is frequently used to enable a first assessment of a pathogen’s fitness, replication, and pathogenesis for influenza A and B viruses. We showed that DBA/2 mice are a relevant in vivo model for the study of IDV replication. This model will allow for rapid IDV fitness and replication evaluation and will enable phenotypic comparisons between isolated viruses. It will also allow for a better understanding of the immune response induced after IDV infection.

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Replication and Transmission of the Novel Bovine Influenza D Virus in a Guinea Pig Model

Journal of Virology ◽

10.1128/jvi.01630-15 ◽

2015 ◽

Vol 89 (23) ◽

pp. 11990-12001 ◽

Cited By ~ 40

Author(s):

Chithra Sreenivasan ◽

Milton Thomas ◽

Zizhang Sheng ◽

Ben M. Hause ◽

Emily A. Collin ◽

...

Keyword(s):

Influenza Virus ◽

Respiratory Tract ◽

Guinea Pigs ◽

Clinical Signs ◽

Suitable Model ◽

Upper Respiratory Tract ◽

Experimental Conditions ◽

Primary Host ◽

Transmission Potential ◽

Sentinel Animals

ABSTRACTInfluenza D virus (FLUDV) is a novel influenza virus that infects cattle and swine. The goal of this study was to investigate the replication and transmission of bovine FLUDV in guinea pigs. Following direct intranasal inoculation of animals, the virus was detected in nasal washes of infected animals during the first 7 days postinfection. High viral titers were obtained from nasal turbinates and lung tissues of directly inoculated animals. Further, bovine FLUDV was able to transmit from the infected guinea pigs to sentinel animals by means of contact and not by aerosol dissemination under the experimental conditions tested in this study. Despite exhibiting no clinical signs, infected guinea pigs developed seroconversion and the viral antigen was detected in lungs of animals by immunohistochemistry. The observation that bovine FLUDV replicated in the respiratory tract of guinea pigs was similar to observations described previously in studies of gnotobiotic calves and pigs experimentally infected with bovine FLUDV but different from those described previously in experimental infections in ferrets and swine with a swine FLUDV, which supported virus replication only in the upper respiratory tract and not in the lower respiratory tract, including lung. Our study established that guinea pigs could be used as an animal model for studying this newly emerging influenza virus.IMPORTANCEInfluenza D virus (FLUDV) is a novel emerging pathogen with bovine as its primary host. The epidemiology and pathogenicity of the virus are not yet known. FLUDV also spreads to swine, and the presence of FLUDV-specific antibodies in humans could indicate that there is a potential for zoonosis. Our results showed that bovine FLUDV replicated in the nasal turbinate and lungs of guinea pigs at high titers and was also able to transmit from an infected animal to sentinel animals by contact. The fact that bovine FLUDV replicated productively in both the upper and lower respiratory tracts of guinea pigs, similarly to virus infection in its native host, demonstrates that guinea pigs would be a suitable model host to study the replication and transmission potential of bovine FLUDV.

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Type I Interferon Signaling Is a Common Factor Driving Streptococcus pneumoniae and Influenza A Virus Shedding and Transmission

mBio ◽

10.1128/mbio.03589-20 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Tonia Zangari ◽

Mila B. Ortigoza ◽

Kristen L. Lokken-Toyli ◽

Jeffrey N. Weiser

Keyword(s):

Streptococcus Pneumoniae ◽

Respiratory Tract ◽

Influenza A Virus ◽

Influenza A ◽

Common Factor ◽

Type I ◽

Upper Respiratory Tract ◽

Content Type ◽

Infant Mouse ◽

Upper Respiratory

ABSTRACT The dynamics underlying respiratory contagion (the transmission of infectious agents from the airways) are poorly understood. We investigated host factors involved in the transmission of the leading respiratory pathogen Streptococcus pneumoniae. Using an infant mouse model, we examined whether S. pneumoniae triggers inflammatory pathways shared by influenza A virus (IAV) to promote nasal secretions and shedding from the upper respiratory tract to facilitate transit to new hosts. Here, we show that amplification of the type I interferon (IFN-I) response is a critical host factor in this process, as shedding and transmission by both IAV and S. pneumoniae were decreased in pups lacking the common IFN-I receptor (Ifnar1−/− mice). Additionally, providing exogenous recombinant IFN-I to S. pneumoniae-infected pups was sufficient to increase bacterial shedding. The expression of IFN-stimulated genes (ISGs) was upregulated in S. pneumoniae-infected wild-type (WT) but not Ifnar1−/− mice, including genes involved in mucin type O-glycan biosynthesis; this correlated with an increase in secretions in S. pneumoniae- and IAV-infected WT compared to Ifnar1−/− pups. S. pneumoniae stimulation of ISGs was largely dependent on its pore-forming toxin, pneumolysin, and coinfection with IAV and S. pneumoniae resulted in synergistic increases in ISG expression. We conclude that the induction of IFN-I signaling appears to be a common factor driving viral and bacterial respiratory contagion. IMPORTANCE Respiratory tract infections are a leading cause of childhood mortality and, globally, Streptococcus pneumoniae is the leading cause of mortality due to pneumonia. Transmission of S. pneumoniae primarily occurs through direct contact with respiratory secretions, although the host and bacterial factors underlying transmission are poorly understood. We examined transmission dynamics of S. pneumoniae in an infant mouse model and here show that S. pneumoniae colonization of the upper respiratory tract stimulates host inflammatory pathways commonly associated with viral infections. Amplification of this response was shown to be a critical host factor driving shedding and transmission of both S. pneumoniae and influenza A virus, with infection stimulating expression of a wide variety of genes, including those involved in the biosynthesis of mucin, a major component of respiratory secretions. Our findings suggest a mechanism facilitating S. pneumoniae contagion that is shared by viral infection.

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Pathogenesis and Transmission of Genetically Diverse Swine-Origin H3N2 Variant Influenza A Viruses from Multiple Lineages Isolated in the United States, 2011–2016

Journal of Virology ◽

10.1128/jvi.00665-18 ◽

2018 ◽

Vol 92 (16) ◽

Cited By ~ 7

Author(s):

Xiangjie Sun ◽

Joanna A. Pulit-Penaloza ◽

Jessica A. Belser ◽

Claudia Pappas ◽

Melissa B. Pearce ◽

...

Keyword(s):

United States ◽

Respiratory Tract ◽

Influenza A ◽

Seasonal Influenza ◽

The United States ◽

Influenza Viruses ◽

Upper Respiratory Tract ◽

Pandemic Preparedness

ABSTRACTWhile several swine-origin influenza A H3N2 variant (H3N2v) viruses isolated from humans prior to 2011 have been previously characterized for their virulence and transmissibility in ferrets, the recent genetic and antigenic divergence of H3N2v viruses warrants an updated assessment of their pandemic potential. Here, four contemporary H3N2v viruses isolated during 2011 to 2016 were evaluated for their replicative ability in bothin vitroandin vivoin mammalian models as well as their transmissibility among ferrets. We found that all four H3N2v viruses possessed similar or enhanced replication capacities in a human bronchial epithelium cell line (Calu-3) compared to a human seasonal influenza virus, suggestive of strong fitness in human respiratory tract cells. The majority of H3N2v viruses examined in our study were mildly virulent in mice and capable of replicating in mouse lungs with different degrees of efficiency. In ferrets, all four H3N2v viruses caused moderate morbidity and exhibited comparable titers in the upper respiratory tract, but only 2 of the 4 viruses replicated in the lower respiratory tract in this model. Furthermore, despite efficient transmission among cohoused ferrets, recently isolated H3N2v viruses displayed considerable variance in their ability to transmit by respiratory droplets. The lack of a full understanding of the molecular correlates of virulence and transmission underscores the need for close genotypic and phenotypic monitoring of H3N2v viruses and the importance of continued surveillance to improve pandemic preparedness.IMPORTANCESwine-origin influenza viruses of the H3N2 subtype, with the hemagglutinin (HA) and neuraminidase (NA) derived from historic human seasonal influenza viruses, continue to cross species barriers and cause human infections, posing an indelible threat to public health. To help us better understand the potential risk associated with swine-origin H3N2v viruses that emerged in the United States during the 2011-2016 influenza seasons, we use bothin vitroandin vivomodels to characterize the abilities of these viruses to replicate, cause disease, and transmit in mammalian hosts. The efficient respiratory droplet transmission exhibited by some of the H3N2v viruses in the ferret model combined with the existing evidence of low immunity against such viruses in young children and older adults highlight their pandemic potential. Extensive surveillance and risk assessment of H3N2v viruses should continue to be an essential component of our pandemic preparedness strategy.

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Abstract 17261: Inhibition of Fibrinolysis Attenuates Influenza A-induced Lung Injury

Circulation ◽

10.1161/circ.130.suppl_2.17261 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Luisa Morales-Nebreda ◽

Mesut Eren ◽

Saul Soberanes ◽

Recep Nigdelioglu ◽

Micah Rogel ◽

...

Keyword(s):

Immune Response ◽

Lung Injury ◽

Plasminogen Activator ◽

Influenza A ◽

The United States ◽

Morbidity And Mortality ◽

Tissue Type ◽

Type I ◽

Wild Type ◽

Pai 1

Rationale: Influenza A virus (IAV) is the leading cause of death from an infectious cause and ranks 8th in the list of attributable annual mortality in the United States. Currently available antiviral treatments are limited and may become ineffective as resistant strains emerge. The coexistence of hemostatic alterations with inflammatory responses to viral infections support the idea that common molecular mechanisms contribute to the regulation of these systems. Previous studies demonstrated that IAV induces the activation of both coagulation and fibrinolytic pathways, and that the impairment of the latter is mainly attributable to high levels of plasminogen activator inhibitor type I (PAI-1), the major inhibitor of tissue-type plasminogen activator (t-PA). Interferon-α (IFN-α) plays a key role in the control of viral replication and overall shaping of the immune response. We sought to determine whether PAI-1, plays a role in the immune response and morbidity and mortality associated with IAV infection. Methods: Wild-type (C57BL/6J), PAI-1-/-, t-PA-/- and PAI-1 stab (transgenic mice expressing an active form of human PAI-1) mice were treated intratracheally with IAV (A/WSN/33 [H1N1] 500 pfu/mouse in 50μl PBS). We assessed the levels of IFN-α in bronchoalveolar lavage fluid (BALF) on day 2 and 4, and influenza A-induced morbidity (weight loss) and mortality. Results: Compared with wild-type mice, PAI-1-/- mice had increased IAV-induced morbidity and mortality. In contrast, both PAI-1 stab and t-PA-/- mice had improved survival. In wild-type mice, IAV induced a significant elevation IFN-α levels in BALF. PAI-1 stab mice had a 2-fold increase, while PAI-1-/-mice had a 69% reduction in IFN-α levels in BALF compared to wild-type mice. Conclusions: Inhibition of fibrinolysis by means of genetic overexpression of PAI-1 or deletion of t-PA augments the antiviral response and attenuates the morbidity and mortality associated with IAV infection. These results suggest an important functional role for PAI-1 and fibrinolysis in the pathogenesis of influenza A infection. Modulation of the fibrinolytic pathway or PAI-1 may potentially be useful as a target for novel therapeutics in the management of IAV-induced lung injury.

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Principles of Judicious Use of Antimicrobial Agents for Pediatric Upper Respiratory Tract Infections

PEDIATRICS ◽

10.1542/peds.101.s1.163 ◽

1998 ◽

Vol 101 (Supplement_1) ◽

pp. 163-165 ◽

Cited By ~ 11

Author(s):

Scott F. Dowell ◽

S. Michael Marcy ◽

William R. Phillips ◽

Michael A. Gerber ◽

Benjamin Schwartz

Keyword(s):

Respiratory Tract ◽

Antimicrobial Agents ◽

Respiratory Infections ◽

The United States ◽

Antimicrobial Treatment ◽

Antimicrobial Use ◽

Upper Respiratory Tract ◽

Oral Agents ◽

Upper Respiratory ◽

Tract Infections

This article introduces a set of principles to define judicious antimicrobial use for five conditions that account for the majority of outpatient antimicrobial use in the United States. Data from the National Center for Health Statistics indicate that in recent years, approximately three fourths of all outpatient antibiotics have been prescribed for otitis media, sinusitis, bronchitis, pharyngitis, or nonspecific upper respiratory tract infection.1Antimicrobial drug use rates are highest for children1; therefore, the pediatric age group represents the focus for the present guidelines. The evidence-based principles presented here are focused on situations in which antimicrobial therapy could be curtailed without compromising patient care. They are not formulated as comprehensive management strategies. For most upper respiratory infections that require antimicrobial treatment, there are several appropriate oral agents from which to choose. Although the general principles of selecting narrow-spectrum agents with the fewest side effects and lowest cost are important, the principles that follow include few specific antibiotic selection recommendations.

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An outbreak of SARS-CoV-2 with high mortality in mink (Neovison vison) on multiple Utah farms

10.1101/2021.06.09.447754 ◽

2021 ◽

Author(s):

Chrissy Eckstrand ◽

Tom Baldwin ◽

Mia Kim Torchetti ◽

Mary Lea Killian ◽

Kerry A Rood ◽

...

Keyword(s):

Respiratory Tract ◽

Clinical Signs ◽

Viral Transmission ◽

Viral Rna ◽

Upper Respiratory Tract ◽

Tracheobronchial Lymph Node ◽

Multiple Organs ◽

Upper Respiratory ◽

Polymerase Chain

The breadth of animal hosts that are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and may serve as reservoirs for continued viral transmission are not known entirely. In August 2020, an outbreak of SARS-CoV-2 occurred in multiple mink farms in Utah and was associated with high mink mortality and rapid viral transmission between animals. The outbreak's epidemiology, pathology, molecular characterization, and tissue distribution of virus within infected mink is provided. Infection of mink was likely by reverse zoonosis. Once established, infection spread rapidly between independently housed animals and farms, and caused severe respiratory disease and death. Clinical signs were most notably sudden death, anorexia, and increased respiratory effort. Gross pathology examination revealed severe pulmonary congestion and edema. Microscopically there was pulmonary edema with moderate vasculitis, perivasculitis, and fibrinous interstitial pneumonia. Reverse transcriptase polymerase chain reaction (RT-PCR) of tissues collected at necropsy demonstrated the presence of SARS-CoV-2 viral RNA in multiple organs including nasal turbinates, lung, tracheobronchial lymph node, epithelial surfaces, and others. Whole genome sequencing from multiple mink was consistent with published SARS-CoV-2 genomes with few polymorphisms. The Utah mink SARS-CoV-2 strain fell into Clade GH, which is unique among mink and other animal strains sequenced to date and did not share other spike RBD mutations Y453F and F486L found in mink. Localization of viral RNA by in situ hybridization revealed a more localized infection, particularly of the upper respiratory tract. Mink in the outbreak reported herein had high levels of virus in the upper respiratory tract associated with mink-to-mink transmission in a confined housing environment and were particularly susceptible to disease and death due to SARS-CoV-2 infection.

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RNA sensors as a mechanism of innate immune evasion among SARS-CoV2, HIV and Nipah viruses

Current Protein and Peptide Science ◽

10.2174/1389203722666210322142725 ◽

2021 ◽

Vol 22 ◽

Author(s):

Dalia Cicily Kattiparambil Dixon ◽

Chameli Ratan ◽

Bhagyalakshmi Nair ◽

Sabitha Mangalath ◽

Rachy Abraham ◽

...

Keyword(s):

Immune Response ◽

Innate Immunity ◽

Innate Immune Response ◽

Vaccine Development ◽

Innate Immune ◽

Interferon Response ◽

Host Immune System ◽

Type I ◽

Adaptive Responses ◽

Rna Sensors

: Innate immunity is the first line of defence elicited by the host immune system to fight against invading pathogens such as viruses and bacteria. From this elementary immune response, the more complex antigen-specific adaptive responses are recruited to provide a long-lasting memory against the pathogens. Innate immunity gets activated when the host cell utilizes a diverse set of receptors known as pattern recognition receptors (PRR) to recognize the viruses that have penetrated the host and respond with cellular processes like complement system, phagocytosis, cytokine release and inflammation and destruction of NK cells. Viral RNA or DNA or viral intermediate products are recognized by receptors like toll-like receptors(TLRs), nucleotide oligomerization domain(NOD)-like receptors (NLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) thereby, inducing type I interferon response (IFN) and other proinflammatory cytokines in infected cells or other immune cells. But certain viruses can evade the host innate immune response to replicate efficiently, triggering the spread of the viral infection. The present review describes the similarity in the mechanism chosen by viruses from different families -HIV, SARS-CoV2 and Nipah viruses to evade the innate immune response and how efficiently they establish the infection in the host. The review also addresses the stages of developments of various vaccines against these viral diseases and the challenges encountered by the researchers during vaccine development.

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Bacterial Infections of the Adult Upper Respiratory Tract

10.2310/fm.1237 ◽

2019 ◽

Author(s):

Laura K Certain ◽

Miriam B Barshak

Keyword(s):

Respiratory Tract ◽

Bacterial Infections ◽

Respiratory Tract Infections ◽

Respiratory Infections ◽

Group A Streptococcus ◽

The United States ◽

Controlled Study ◽

Upper Respiratory Tract ◽

Upper Respiratory ◽

Tract Infections

Upper respiratory tract infections are the most common maladies experienced by humankind.1 The majority are caused by respiratory viruses. A Dutch case-controlled study of primary care patients with acute respiratory tract infections found that viruses accounted for 58% of cases; rhinovirus was the most common (24%), followed by influenza virus type A (11%) and coronaviruses (7%). Group A streptococcus (GAS) was responsible for 11%, and 3% of patients had mixed infections. Potential pathogens were detected in 30% of control patients who were free of acute respiratory symptoms; rhinovirus was the most common.2 Given the increasing problem of antibiotic resistance and the increasing awareness of the importance of a healthy microbiome, antibiotic use for upper respiratory infections should be reserved for those patients with clear indications for treatment. A recent study of adult outpatient visits in the United States found that respiratory complaints accounted for 150 antibiotic prescriptions per 1,000 population annually, yet the expected “appropriate” rate would be 45.3 In other words, most antibiotic prescriptions for these complaints are unnecessary. Similarly, a study in the United Kingdom found that general practitioners prescribed antibiotics to about half of all patients presenting with an upper respiratory infection, even though most of these infections are viral.4 This review contains 5 figures, 16 tables, and 82 references. Keywords: infection, airway, sinusitis, otitis media, otitis externa, pharyngitis, epiglottitis, abscess

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Exploring the microbiota of upper respiratory tract during the development of pneumonia in a mouse model

PLoS ONE ◽

10.1371/journal.pone.0222589 ◽

2019 ◽

Vol 14 (9) ◽

pp. e0222589

Author(s):

Yoshitomo Morinaga ◽

Yuki Take ◽

Daisuke Sasaki ◽

Kenji Ota ◽

Norihito Kaku ◽

...

Keyword(s):

Mouse Model ◽

Respiratory Tract ◽

Upper Respiratory Tract ◽

Upper Respiratory

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The Role of the Immune Response in the Pathogenesis of Bronchiectasis

BioMed Research International ◽

10.1155/2018/6802637 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Paul T. King

Keyword(s):

Immune Response ◽

Inflammatory Response ◽

Respiratory Tract ◽

Lower Respiratory Tract ◽

Therapeutic Potential ◽

Small Airways ◽

Upper Respiratory Tract ◽

Causative Factors ◽

Triggering Factor

Bronchiectasis is a prevalent respiratory condition characterised by permanent and abnormal dilation of the lung airways (bronchi). There are a large variety of causative factors that have been identified for bronchiectasis; all of these compromise the function of the immune response to fight infection. A triggering factor may lead to the establishment of chronic infection in the lower respiratory tract. The bacteria responsible for the lower respiratory tract infection are usually found as commensals in the upper respiratory tract microbiome. The consequent inflammatory response to infection is largely responsible for the pathology of this condition. Both innate and adaptive immune responses are activated. The literature has highlighted the central role of neutrophils in the pathogenesis of bronchiectasis. Proteases produced in the lung by the inflammatory response damage the airways and lead to the pathological dilation that is the pathognomonic feature of bronchiectasis. The small airways demonstrate infiltration with lymphoid follicles that may contribute to localised small airway obstruction. Despite aggressive treatment, most patients will have persistent disease. Manipulating the immune response in bronchiectasis may potentially have therapeutic potential.

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