Prophylactic administration of bacterially derived immunomodulators improves the outcome of influenza virus infection in a murine model.
Prophylactic or therapeutic immunomodulation is an antigen-independent strategy that induces nonspecific immune system activation, thereby enhancing host defense to disease. In this study, we investigated the effect of prophylactic immunomodulation on the outcome of influenza virus infection using three bacterially derived immune-enhancing agents known for promoting distinct immunological profiles. BALB/c mice were treated nasally with either cholera toxin (CT), a mutant form of the CT-related Escherichia coli heat-labile enterotoxin designated LT(R192G), or CpG oligodeoxynucleotide. Mice were subsequently challenged with a lethal dose of influenza A/PR/8/34 virus 24 h after the last immunomodulation treatment and either monitored for survival or sacrificed postchallenge for viral and immunological analysis. Treatment with the three immunomodulators prevented or delayed mortality and weight loss, but only CT and LT(R192G) significantly reduced initial lung viral loads as measured by plaque assay. Analysis performed 4 days postinfection indicated that prophylactic treatments with CT, LT(R192G), or CpG resulted in significantly increased numbers of CD4 T cells, B cells, and dendritic cells and altered costimulatory marker expression in the airways of infected mice, coinciding with reduced expression of pulmonary chemokines and the appearance of inducible bronchus-associated lymphoid tissue-like structures in the lungs. Collectively, these results suggest that, despite different immunomodulatory mechanisms, CT, LT(R192G), and CpG induce an initial inflammatory process and enhance the immune response to primary influenza virus challenge while preventing potentially damaging chemokine expression. These studies provide insight into the immunological parameters and immune modulation strategies that have the potential to enhance the nonspecific host response to influenza virus infection.
Norton
Elizabeth B
EB
Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Clements
John D
JD
Voss
Thomas G
TG
Cárdenas-Freytag
Lucia
L
D000281:Administration, Intranasal; D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D001835:Body Weight; D002772:Cholera Toxin / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007107:Immune System / Q000502:physiology; D007155:Immunologic Factors / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D007249:Inflammation / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D007251:Influenza, Human / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D009976:Orthomyxoviridae Infections / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D015996:Survival Rate; D016896:Treatment Outcome; D019562:Viral Load
D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D007155:Immunologic Factors; D009838:Oligodeoxyribonucleotides; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli