Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 feeding enhances humoral immune responses, which are suppressed by the antiviral neuraminidase inhibitor oseltamivir in influenza A virus-infected mice

J Dairy Sci. 2019 Nov;102(11):9559-9569. doi: 10.3168/jds.2019-16268. Epub 2019 Sep 5.


Antiviral neuraminidase inhibitors, such as oseltamivir, zanamivir, and peramivir, are widely used for treatment of influenza virus infection. We reported previously that oseltamivir inhibits the viral growth cycle, ameliorates symptoms, and reduces viral antigen quantities. Suppressed viral antigen production, however, induces a reduction of acquired antiviral humoral immunity, and increases the incidence of re-infection rate in the following year. To achieve effective treatment of influenza virus infection, it is necessary to overcome these adverse effects of antiviral neuraminidase inhibitors. Feeding of yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus (L. bulgaricus) OLL1073R-1 is reported to have immune-stimulatory effects on influenza virus infection in mice and humans. In the present study, we assessed the effect of feeding L. bulgaricus OLL1073R-1 yogurt cultures (YC) on local and systemic humoral immune responses, which were suppressed by oseltamivir treatment, in mice infected with influenza A virus. Yogurt culture (1.14 × 108 cfu/0.4 mL per mouse per day) or sterile water (vehicle) was administered by intragastric gavage for 35 d. At d 22, influenza A virus/Puerto Rico/8/34 (H1N1) (PR8; 0.5 pfu/15 μL per mouse) was instilled intranasally, followed immediately by oral administration of oseltamivir (50 μg/100 μL per mouse, twice daily) or 5% methylcellulose (100 μL/mouse) as a vehicle for 13 d. Titers of anti-PR8-specific IgG and IgA in serum and mucosal secretory IgA (S-IgA) and IgG in bronchoalveolar lavage fluid (BALF) were analyzed by ELISA at 14 d after infection. Oseltamivir significantly suppressed the induction of anti-PR8-specific IgG and IgA in serum and S-IgA and IgG in BALF after infection. Feeding YC mildly but significantly stimulated production of PR8-specific IgA in serum, S-IgA in BALF, and IgG in serum without changing the IgG2a:IgG1 ratio. We analyzed the neutralizing activities against PR8 in serum and BALF and found that oseltamivir also reduced protective immunity, and YC feeding abrogated this effect. The immune-stimulatory tendency of YC on anti-PR8-specific IgA and IgG titers in serum and BALF was also detected in mice re-infected with PR8, but the effect was insignificant, unlike the effect of YC in the initial infection.

Keywords: immunomodulatory effects; influenza A virus infection; oseltamivir; yogurt culture.

MeSH terms

  • Animal Feed
  • Animals
  • Antiviral Agents / adverse effects
  • Antiviral Agents / antagonists & inhibitors
  • Antiviral Agents / therapeutic use*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Immunity, Humoral / drug effects*
  • Influenza A Virus, H1N1 Subtype / drug effects
  • Lactobacillus delbrueckii* / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Neuraminidase / antagonists & inhibitors*
  • Orthomyxoviridae Infections / diet therapy
  • Orthomyxoviridae Infections / drug therapy
  • Orthomyxoviridae Infections / immunology*
  • Oseltamivir / adverse effects
  • Oseltamivir / antagonists & inhibitors
  • Oseltamivir / therapeutic use*
  • Probiotics / therapeutic use*
  • Viral Proteins / antagonists & inhibitors*
  • Yogurt


  • Antiviral Agents
  • Enzyme Inhibitors
  • Viral Proteins
  • Oseltamivir
  • NA protein, influenza A virus
  • Neuraminidase