Pneumocystis infection enhances antibody-mediated resistance to a subsequent influenza infection

Source: Wiley JA, Harmsen AG. Pneumocystis infection enhances antibody-mediated

resistance to a subsequent influenza infection. J Immunol. 2008 Apr

15;180(8):5613-24. PubMed PMID: 18390746; PubMed Central PMCID: PMC2600725.

 

 

In the lung concurrent immune responses can occur. These occur due to

1. Simultaneous and/or consecutive exposure to multiple pathogens or immunogens
   
2. Exposure of asthamatic patients to pulmonary pathogens
   
3. When pathogen associated immune responses interact with responses to underlying chronic pulmonary diseases involving infections or COPD or emphysema
   

The progression of concurrent immune responses in the lung can lead to beneficial or detrimental outcomes. In the present paper, the authors tried to further look at this area by using co-infection with two different but regularly encountered pulmonary pathogens that elicit opposing immune responses. They used Pneumocystis murina, which elicits a type 2 immune response and influenza type A virus, which elicits a type 1 immune response.

The major results of the studies are as follows:

• Pathogen recovery from lungs: Mice were infected with Pneumocystis-infected lung homogenate and after 2-3 weeks they were infected with influenza. The control mice were given uninfected lung homogenate 2-3 weeks prior to influenza infection. Viral recovery by plaque assay was determined in co-infected mice after 1 week of influenza infection. In another set of experiments the sequence of co-infections was reversed. When Pneumocystis infection was initiated two weeks prior to influenza infection, the recovery of influenza virus decreased 100 fold in comparison to control mice. In contrast, when Pneumocystis infection was initiated three weeks prior to influenza infection, recovery of virus decreased to 10 fold. The authors further examined the rate of clearance of virus in two weeks apart co-infection model and control mice over a 10 day period following virus challenge. The greatest difference in viral clearance among the two groups was observed after seven days. Thus, the results suggested Pneumocystis infection two weeks prior to influenza infection caused reduction in influenza virus recovery.
  
• Analysis of cell recovery in BALF: The lungs of each animal were lavaged 1 week after co-infection with the influenza virus. Lymphocytes and macrophages were present in equal numbers among the two groups during the resolution of influenza infection. In contrast, neutrophils were significantly higher in airways of control mice. Among the co-infected models, neutrophils were same as those present at day 0 of influenza infection after Pneumocystis infection. The eosinophils remained at negligible levels in the influenza only control animals. The number of eosinophils was high both at the time of influenza and during resolution in co-infection models.
  
• Change in weight: The authors also examined change in weights of both groups of animals following influenza infection. Over the 10 days following the influenza infection, co-infected animals lost least amount of weight. In contrast, influenza only control animals continued to lose weight.
  
• Recovery of serum albumin and lactate dehydrogenase in BALF: Levels of albumin and LDH generally increase during lung damage and thus this increase has been used as an indicator of lung damage. In the present study, the authors observed that both albumin and LDH levels remained same at day 0 and day 7 in co-infected animals. In contrast, significant increase in albumin and LDH levels was observed in influenza only control animals.
  
• Recovery of inflammatory cytokines in BALF: The levels of inflammatory cytokines, TNFalpha, IL-10, IFN, IFN-gamma, MCP-1 and IL-6 were significantly reduced in co-infected animals compared to control animals.
  
• Germinal center B cell analysis: The investigators also performed FACS analysis of GC B cell proliferation on spleen and local tracheal-bronchial lymph node (TBLN). The authors observed that GC B cell proliferation was greater in both spleen and TBLN in co-infected animals and in control mice 1 week after influenza infection.
  
• Influenza antibody titers detected in the BALF and serum: In order to determine whether immune response to the Pneumocystis infection altered the local and/or systemic influenza specific antibodies levels, the authors also sought to determine the influenza specific antibodies. They observed that in lungs of co-infected animals, influenza specific IgA, IgG and IgM antibodies appeared earlier and remained at significantly higher levels following influenza infection.
  
• Absence of antibody negates enhanced viral clearance in co-infected mice: The authors found out that there is rapid appearance of influenza specific antibodies, which could be responsible for effective viral clearance. Thus, to determine whether the enhanced rate of viral clearance in case of co-infected animals was due to influenza specific antibodies, the authors co-infected uMT (mice generated by disruption of one of the membrane exons of the u-chain gene and have no detectable B cells or circulating antibody but have normal T cells), SCID and immunocompetent mice. They found that virus recovery in uMT co-infected mice and uMT- influenza only mice was same at seven days prior to influenza infection. The levels of viral recovery were equivalent between all of the SCID and uMT infection groups. Among the wild type mice, significant differences in virus recovery were observed among the co-infected mice and influenza only infected mice.