Lethal Synergism between Influenza Virus andStreptococcus pneumoniae:Characterization of a Mouse Model and the Role of Platelet‐Activating Factor Receptor

Although influenza infection alone may lead to pneumonia, secondary bacterial infections are a much more common cause of pneumonia. Streptococcus pneumoniae is the most frequently isolated causative pathogen during postinfluenza pneumonia. Considering that S. pneumoniae utilizes the platelet-activating factor receptor (PAFR) to invade the respiratory epithelium and that the PAFR is upregulated during viral infection, we here used PAFR gene-deficient (PAFR−/−) mice to determine the role of this receptor during postinfluenza pneumococcal pneumonia. Viral clearance was similar in wild-type and PAFR−/− mice, and influenza virus was completely removed from the lungs at the time mice were inoculated with S. pneumoniae ( day 14 after influenza infection). PAFR−/− mice displayed a significantly reduced bacterial outgrowth in their lungs, a diminished dissemination of the infection, and a prolonged survival. Pulmonary levels of IL-10 and KC were significantly lower in PAFR−/− mice, whereas IL-6 and TNF-α were only trendwise lower. These data indicate that the pneumococcus uses the PAFR leading to severe pneumonia in a host previously exposed to influenza A.

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Activation and Regulation of Platelet-Activating Factor Receptor: Role of Gi and Gq in Receptor-Mediated Chemotactic, Cytotoxic, and Cross-Regulatory Signals

The Journal of Immunology ◽

10.4049/jimmunol.177.5.3242 ◽

2006 ◽

Vol 177 (5) ◽

pp. 3242-3249 ◽

Cited By ~ 35

Author(s):

Stephan L. Brown ◽

Venkatakrishna R. Jala ◽

Sandeep K. Raghuwanshi ◽

Mohd W. Nasser ◽

Bodduluri Haribabu ◽

...

Keyword(s):

Platelet Activating Factor ◽

Platelet Activating Factor Receptor

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Role of cytoplasmic tail phosphorylation sites of platelet-activating factor receptor in agonist-induced desensitization.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(17)31811-2 ◽

1994 ◽

Vol 269 (35) ◽

pp. 22453-22458

Author(s):

T. Takano ◽

Z. Honda ◽

C. Sakanaka ◽

T. Izumi ◽

K. Kameyama ◽

...

Keyword(s):

Platelet Activating Factor ◽

Cytoplasmic Tail ◽

Phosphorylation Sites ◽

Platelet Activating Factor Receptor

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Immunomodulation by n-3- versus n-6-rich lipid emulsions in murine acute lung injury—Role of platelet-activating factor receptor

Critical Care Medicine ◽

10.1097/01.ccm.0000253811.74112.b6 ◽

2007 ◽

Vol 35 (2) ◽

pp. 544-554 ◽

Cited By ~ 22

Author(s):

Martina Barbara Schaefer ◽

Juliane Ott ◽

Andrea Mohr ◽

Ming Hua Bi ◽

Andrea Grosz ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Platelet Activating Factor ◽

Lipid Emulsions ◽

Platelet Activating Factor Receptor

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Systemic Platelet-Activating Factor-Receptor Agonism Enhances Non-Melanoma Skin Cancer Growth

International Journal of Molecular Sciences ◽

10.3390/ijms19103109 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3109 ◽

Cited By ~ 2

Author(s):

Eric Romer ◽

Anita Thyagarajan ◽

Smita Krishnamurthy ◽

Christine Rapp ◽

Langni Liu ◽

...

Keyword(s):

Skin Cancer ◽

Platelet Activating Factor ◽

Chemical Carcinogenesis ◽

Melanocytic Nevus ◽

Non Melanoma Skin Cancer ◽

Cancer Models ◽

Platelet Activating Factor Receptor ◽

Melanoma Skin ◽

Topical Applications

Platelet-activating factor-receptor (PAF-R) agonists are pleiotropic lipid factors that influence multiple biological processes, including the induction and resolution of inflammation as well as immunosuppression. PAF-R agonists have been shown to modulate tumorigenesis and/or tumor growth in various skin cancer models by suppressing either cutaneous inflammation and/or anti-tumoral adaptive immunity. We have previously shown that a chronic systemic PAF-R agonist administration of mice enhances the growth of subcutaneously implanted melanoma tumors. Conversely, chronic topical applications of a PAF-R agonist suppressed non-melanoma skin cancer (NMSC) in a topical chemical carcinogenesis model (dimethylbenz[a]anthracene/phorbol 12-myristate 13-acetate (DMBA/PMA)) in-part via anti-inflammatory effects. These results indicate that the context of PAF-R agonist exposure via either chronic cutaneous or systemic administration, result in seemingly disparate effects on tumor promotion. To further dissect the contextual role of PAF-R agonism on tumorigenesis, we chronically administered systemic PAF-R agonist, carbamoyl-PAF (CPAF) to mice under a cutaneous chemical carcinogenesis protocol, recently characterized to initiate both NMSC and melanocytic nevus formation that can progress to malignant melanoma. Our results showed that while systemic CPAF did not modulate melanocytic nevus formation, it enhanced the growth of NMSC tumors.

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

mBio ◽

10.1128/mbio.02359-18 ◽

2018 ◽

Vol 9 (6) ◽

Cited By ~ 5

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.

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