Ability of Antibiotic-Resistant Nonvaccine-Type Pneumococcal Clones to Cause Otitis Media in an Infant Mouse Model of Pneumococcal–Influenza Virus Coinfection

2016 ◽  
Vol 22 (1) ◽  
pp. 97-101 ◽  
Author(s):  
Nelson Frazão ◽  
Peter Hermans ◽  
Saskia van Selm ◽  
Raquel Sá-Leão ◽  
Hermínia de Lencastre ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Mouse Model ◽  
Otitis Media ◽  
Antibiotic Resistant ◽  
Infant Mouse

scholarly journals An Infant Mouse Model of Influenza Virus Transmission Demonstrates the Role of Virus-Specific Shedding, Humoral Immunity, and Sialidase Expression by ColonizingStreptococcus pneumoniae

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Mila Brum Ortigoza ◽  
Simone B. Blaser ◽  
M. Ammar Zafar ◽  
Alexandria J. Hammond ◽  
Jeffrey N. Weiser
Keyword(s):  
Influenza Virus ◽  
Mouse Model ◽  
Virus Strain ◽  
Humoral Immunity ◽  
Disease Spread ◽  
Upper Respiratory Tract ◽  
Content Type ◽  
Infant Mouse ◽  
Primary Model

ABSTRACTThe pandemic potential of influenza A viruses (IAV) depends on the infectivity of the host, transmissibility of the virus, and susceptibility of the recipient. While virus traits supporting IAV transmission have been studied in detail using ferret and guinea pig models, there is limited understanding of host traits determining transmissibility and susceptibility because current animal models of transmission are not sufficiently tractable. Although mice remain the primary model to study IAV immunity and pathogenesis, the efficiency of IAV transmission in adult mice has been inconsistent. Here we describe an infant mouse model that supports efficient transmission of IAV. We demonstrate that transmission in this model requires young age, close contact, shedding of virus particles from the upper respiratory tract (URT) of infected pups, the use of a transmissible virus strain, and a susceptible recipient. We characterize shedding as a marker of infectiousness that predicts the efficiency of transmission among different influenza virus strains. We also demonstrate that transmissibility and susceptibility to IAV can be inhibited by humoral immunity via maternal-infant transfer of IAV-specific immunoglobulins and modifications to the URT milieu, via sialidase activity of colonizingStreptococcus pneumoniae. Due to its simplicity and efficiency, this model can be used to dissect the host’s contribution to IAV transmission and explore new methods to limit contagion.IMPORTANCEThis study provides insight into the role of the virus strain, age, immunity, and URT flora on IAV shedding and transmission efficiency. Using the infant mouse model, we found that (i) differences in viral shedding of various IAV strains are dependent on specific hemagglutinin (HA) and/or neuraminidase (NA) proteins, (ii) host age plays a key role in the efficiency of IAV transmission, (iii) levels of IAV-specific immunoglobulins are necessary to limit infectiousness, transmission, and susceptibility to IAV, and (iv) expression of sialidases by colonizingS. pneumoniaeantagonizes transmission by limiting the acquisition of IAV in recipient hosts. Our findings highlight the need for strategies that limit IAV shedding and the importance of understanding the function of the URT bacterial composition in IAV transmission. This work reinforces the significance of a tractable animal model to study both viral and host traits affecting IAV contagion and its potential for optimizing vaccines and therapeutics that target disease spread.

scholarly journals An infant mouse model of influenza virus transmission demonstrates the role of virus-specific shedding, humoral immunity, and sialidase expression by colonizingStreptococcus pneumoniae

2018 ◽  
Author(s):  
Mila Brum Ortigoza ◽  
Simone Blaser ◽  
M. Ammar Zafar ◽  
Alexandria Hammond ◽  
Jeffrey N. Weiser
Keyword(s):  
Influenza Virus ◽  
Mouse Model ◽  
Virus Strain ◽  
Humoral Immunity ◽  
Close Contact ◽  
Disease Spread ◽  
Upper Respiratory Tract ◽  
Infant Mouse ◽  
Primary Model

ABSTRACTThe pandemic potential of influenza A viruses (IAV) depends on the infectivity of the host, transmissibility of the virus, and susceptibility of the recipient. While virus traits supporting IAV transmission have been studied in detail using ferret and guinea pig models, there is limited understanding of host traits determining transmissibility and susceptibility because current animal models of transmission are not sufficiently tractable. Although mice remain the primary model to study IAV immunity and pathogenesis, the efficiency of IAV transmission in adult mice has been inconsistent. Here we describe an infant mouse model which support efficient transmission of IAV. We demonstrate that transmission in this model requires young age, close contact, shedding of virus particles from the upper respiratory tract (URT) of infected pups, the use of a transmissible virus strain, and a susceptible recipient. We characterize shedding as a marker of infectiousness that predicts the efficiency of transmission among different influenza virus strains. We also demonstrate that transmissibility and susceptibility to IAV can be inhibited by humoral immunity via maternal-infant transfer of IAV-specific immunoglobulins, and modifications to the URT milieu, via sialidase activity of colonizingStreptococcus pneumoniae(Spn). Due to its simplicity and efficiency, this model can be used to dissect the host’s contribution to IAV transmission and explore new methods to limit contagion.IMPORTANCEThis study provides insight into the role of the virus strain, age, immunity, and URT flora on IAV shedding and transmission efficiency. Using the infant mouse model, we found that: (a) differences in viral shedding of various IAV strains is dependent on specific hemagglutinin (HA) and/or neuraminidase (NA) proteins; (b) host age plays a key role in the efficiency of IAV transmission; (c) levels of IAV-specific immunoglobulins are necessary to limit infectiousness, transmission, and susceptibility to IAV; and (d) expression of sialidases by colonizing Spn antagonize transmission by limiting the acquisition of IAV in recipient hosts. Our findings highlight the need for strategies that limit IAV shedding, and the importance of understanding the function of the URT bacterial composition in IAV transmission. This work reinforces the significance of a tractable animal model to study both viral and host traits affecting IAV contagion, and its potential for optimizing vaccines and therapeutics that target disease spread.

scholarly journals Influenza-Induced Inflammation Drives Pneumococcal Otitis Media

2013 ◽  
Vol 81 (3) ◽  
pp. 645-652 ◽  
Author(s):  
Kirsty R. Short ◽  
Patrick C. Reading ◽  
Lorena E. Brown ◽  
John Pedersen ◽  
Brad Gilbertson ◽  
...  
Keyword(s):  
Otitis Media ◽  
Middle Ear ◽  
Influenza A ◽  
Pneumococcal Disease ◽  
Influenza Viruses ◽  
Dependent Manner ◽  
Proinflammatory Response ◽  
Content Type ◽  
Infant Mouse ◽  
Human Middle Ear

ABSTRACTInfluenza A virus (IAV) predisposes individuals to secondary infections with the bacteriumStreptococcus pneumoniae(the pneumococcus). Infections may manifest as pneumonia, sepsis, meningitis, or otitis media (OM). It remains controversial as to whether secondary pneumococcal disease is due to the induction of an aberrant immune response or IAV-induced immunosuppression. Moreover, as the majority of studies have been performed in the context of pneumococcal pneumonia, it remains unclear how far these findings can be extrapolated to other pneumococcal disease phenotypes such as OM. Here, we used an infant mouse model, human middle ear epithelial cells, and a series of reverse-engineered influenza viruses to investigate how IAV promotes bacterial OM. Our data suggest that the influenza virus HA facilitates disease by inducing a proinflammatory response in the middle ear cavity in a replication-dependent manner. Importantly, our findings suggest that it is the inflammatory response to IAV infection that mediates pneumococcal replication. This study thus provides the first evidence that inflammation drives pneumococcal replication in the middle ear cavity, which may have important implications for the treatment of pneumococcal OM.

Two regulatory factors of Vibrio cholerae activating the mannose-sensitive haemagglutinin pilus expression is important for biofilm formation and colonization in mice

Microbiology ◽  
2021 ◽  
Vol 167 (10) ◽  
Author(s):  
Mengting Shi ◽  
Yue Zheng ◽  
Xianghong Wang ◽  
Zhengjia Wang ◽  
Menghua Yang
Keyword(s):  
Mouse Model ◽  
Vibrio Cholerae ◽  
Biofilm Formation ◽  
Type Species ◽  
Wild Type ◽  
Expression Library ◽  
Content Type ◽  
Genomic Expression ◽  
Infant Mouse ◽  
Link Type

Vibrio cholerae the causative agent of cholera, uses a large number of coordinated transcriptional regulatory events to transition from its environmental reservoir to the host intestine, which is its preferred colonization site. Transcription of the mannose-sensitive haemagglutinin pilus (MSHA), which aids the persistence of V. cholerae in aquatic environments, but causes its clearance by host immune defenses, was found to be regulated by a yet unknown mechanism during the infection cycle of V. cholerae . In this study, genomic expression library screening revealed that two regulators, VC1371 and VcRfaH, are able to positively activate the transcription of MSHA operon. VC1371 is localized and active in the cell membrane. Deletion of vc1371 or VcrfaH genes in V. cholerae resulted in less MshA protein production and less efficiency of biofilm formation compared to that in the wild-type strain. An adult mouse model showed that the mutants with vc1371 or VcrfaH deletion colonized less efficiently than the wild-type; the VcrfaH deletion mutant showed less colonization efficiency in the infant mouse model. The findings strongly suggested that the two regulators, namely VC1371 and VcRfaH, which are involved in the regulation of MSHA expression, play an important role in V. cholerae biofilm formation and colonization in mice.

scholarly journals Shape-Memory Nitinol Tympanostomy Tube and All-in-One Introducer Device for Treatment of Otitis Media

2010 ◽  
Vol 4 (2) ◽  
Author(s):  
Michael Loushin ◽  
Keith Leland
Keyword(s):  
Shape Memory ◽  
Otitis Media ◽  
Point Of Care ◽  
The United States ◽  
Tube Placement ◽  
Tympanostomy Tube ◽  
Office Visits ◽  
Antibiotic Resistant ◽  
Bacterial Organism ◽  
Disposable Device

Otitis media is the most common bacterial illness in children, resulting in millions of office visits, antibiotic prescriptions, and surgical procedures annually in the United States. Antibiotics are commonly prescribed and has resulted in increased prevalence of antibiotic resistant strains of organisms. Additionally, patients with otitis media are candidates for tympanocentesis, myringotomy, and tympanostomy tube placement procedures. The ability to safely and efficiently perform these procedures to accurately diagnose, identify the bacterial organism, and treat otitis media with point of care therapy is needed. A shape-memory nitinol tympanostomy tube and an all-in-one introducer device (OtoStent tympanostomy device) currently under development will allow clinicians to safely and efficiently perform myringotomy, tympanocentesis, and tympanostomy tube placement with a single disposable device.

scholarly journals Streptococcus pneumoniae Transmission Is Blocked by Type-Specific Immunity in an Infant Mouse Model

mBio ◽  
2017 ◽  
Vol 8 (2) ◽  
Author(s):  
Tonia Zangari ◽  
Yang Wang ◽  
Jeffrey N. Weiser
Keyword(s):  
Streptococcus Pneumoniae ◽  
Mouse Model ◽  
Pneumococcal Conjugate Vaccine ◽  
Herd Immunity ◽  
Mechanistic Explanation ◽  
Epidemiological Studies ◽  
Contributing Factors ◽  
Infant Mouse ◽  
Major Benefit

ABSTRACT Epidemiological studies on Streptococcus pneumoniae show that rates of carriage are highest in early childhood and that the major benefit of the pneumococcal conjugate vaccine (PCV) is a reduction in the incidence of nasopharyngeal colonization through decreased transmission within a population. In this study, we sought to understand how anti- S. pneumoniae immunity affects nasal shedding of bacteria, the limiting step in experimental pneumococcal transmission. Using an infant mouse model, we examined the role of immunity (passed from mother to pup) on shedding and within-litter transmission of S. pneumoniae by pups infected at 4 days of life. Pups from both previously colonized immune and PCV-vaccinated mothers had higher levels of anti- S. pneumoniae IgG than pups from non-immune or non-vaccinated mothers and shed significantly fewer S. pneumoniae over the first 5 days of infection. By setting up cross-foster experiments, we demonstrated that maternal passage of antibody to pups either in utero or post-natally decreases S. pneumoniae shedding. Passive immunization experiments showed that type-specific antibody to capsular polysaccharide is sufficient to decrease shedding and that the agglutinating function of immunoglobulin is required for this effect. Finally, we established that anti-pneumococcal immunity and anti-PCV vaccination block host-to-host transmission of S. pneumoniae . Moreover, immunity in either the donor or recipient pups alone was sufficient to reduce rates of transmission, indicating that decreased shedding and protection from acquisition of colonization are both contributing factors. Our findings provide a mechanistic explanation for the reduced levels of S. pneumoniae transmission between hosts immune from prior exposure and among vaccinated children. IMPORTANCE Rates of carriage of the bacterial pathogen Streptococcus pneumoniae are highest among young children, and this is the target group for the pneumococcal conjugate vaccine (PCV). Epidemiological studies have suggested that a major benefit of the PCV is a reduction in host-to-host transmission, which also protects the non-vaccinated population (“herd immunity”). In this study, we examined the role of anti-pneumococcal immunity on nasal shedding and transmission of the pathogen using an infant mouse model. We found that shedding is decreased and transmission is blocked by anti-pneumococcal immunity and PCV vaccination. Additionally, transmission rates decreased if either the infected or contact pups were immune, indicating that reduced shedding and protection from the establishment of colonization are both contributing factors. Our study provides a mechanistic explanation for the herd immunity effect seen after the introduction of PCV and identifies potential points of intervention, which may have implications for future vaccine development.

scholarly journals A Host-Restricted Self-Attenuated Influenza Virus Provides Broad Pan-Influenza A Protection in a Mouse Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Minjin Kim ◽  
Yucheol Cheong ◽  
Jinhee Lee ◽  
Jongkwan Lim ◽  
Sanguine Byun ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Protective Efficacy ◽  
Influenza Viruses ◽  
Cross Protection ◽  
Infection Model ◽  
Wild Type ◽  
Group 1

Influenza virus infections can cause a broad range of symptoms, form mild respiratory problems to severe and fatal complications. While influenza virus poses a global health threat, the frequent antigenic change often significantly compromises the protective efficacy of seasonal vaccines, further increasing the vulnerability to viral infection. Therefore, it is in great need to employ strategies for the development of universal influenza vaccines (UIVs) which can elicit broad protection against diverse influenza viruses. Using a mouse infection model, we examined the breadth of protection of the caspase-triggered live attenuated influenza vaccine (ctLAIV), which was self-attenuated by the host caspase-dependent cleavage of internal viral proteins. A single vaccination in mice induced a broad reactive antibody response against four different influenza viruses, H1 and rH5 (HA group 1) and H3 and rH7 subtypes (HA group 2). Notably, despite the lack of detectable neutralizing antibodies, the vaccination provided heterosubtypic protection against the lethal challenge with the viruses. Sterile protection was confirmed by the complete absence of viral titers in the lungs and nasal turbinates after the challenge. Antibody-dependent cellular cytotoxicity (ADCC) activities of non-neutralizing antibodies contributed to cross-protection. The cross-protection remained robust even after in vivo depletion of T cells or NK cells, reflecting the strength and breadth of the antibody-dependent effector function. The robust mucosal secretion of sIgA reflects an additional level of cross-protection. Our data show that the host-restricted designer vaccine serves an option for developing a UIV, providing pan-influenza A protection against both group 1 and 2 influenza viruses. The present results of potency and breadth of protection from wild type and reassortant viruses addressed in the mouse model by single immunization merits further confirmation and validation, preferably in clinically relevant ferret models with wild type challenges.

scholarly journals Surveying the Down syndrome mouse model resource identifies critical regions responsible for chronic otitis media

2013 ◽  
Vol 24 (11-12) ◽  
pp. 439-445 ◽  
Author(s):  
Mahmood F. Bhutta ◽  
Michael T. Cheeseman ◽  
Yann Herault ◽  
Yuejin E. Yu ◽  
Steve D. M. Brown
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Otitis Media ◽  
Chronic Otitis Media ◽  
Critical Regions

scholarly journals Delayed Administration of Recombinant Plasma Gelsolin Improves Survival in a Murine Model of Penicillin-Susceptible and Penicillin-Resistant Pneumococcal Pneumonia

2019 ◽  
Vol 220 (9) ◽  
pp. 1498-1502 ◽  
Author(s):  
Zhiping Yang ◽  
Alice Bedugnis ◽  
Susan Levinson ◽  
Mark Dinubile ◽  
Thomas Stossel ◽  
...  
Keyword(s):  
Weight Loss ◽  
Antimicrobial Resistance ◽  
Mouse Model ◽  
Murine Model ◽  
Pneumococcal Pneumonia ◽  
Preclinical Models ◽  
Antibiotic Resistant ◽  
Plasma Gelsolin ◽  
Beneficial Effects ◽  
Serious Infections

Abstract Therapy to enhance host immune defenses may improve outcomes in serious infections, especially for antibiotic-resistant pathogens. Recombinant human plasma gelsolin (rhu-pGSN), a normally circulating protein, has beneficial effects in diverse preclinical models of inflammation and injury. We evaluated delayed therapy (24–48 hours after challenge) with rhu-pGSN in a mouse model of pneumococcal pneumonia. rhu-pGSN without antibiotics increased survival and reduced morbidity and weight loss after infection with either penicillin-susceptible or penicillin-resistant pneumococci (serotypes 3 and 14, respectively). rhu-pGSN improves outcomes in a highly lethal pneumococcal pneumonia model when given after a clinically relevant delay, even in the setting of antimicrobial resistance.

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