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2019 ; 10
(3
): ä Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Influenza "Trains" the Host for Enhanced Susceptibility to Secondary Bacterial
Infection
#MMPMID31064834
Shirey KA
; Perkins DJ
; Lai W
; Zhang W
; Fernando LR
; Gusovsky F
; Blanco JCG
; Vogel SN
mBio
2019[May]; 10
(3
): ä PMID31064834
show ga
We previously reported that the Toll-like receptor 4 (TLR4) antagonist Eritoran
blocks acute lung injury (ALI) therapeutically in mouse and cotton rat models of
influenza. However, secondary (2°) bacterial infection following influenza virus
infection is associated with excess morbidity and mortality. Wild-type (WT) mice
infected with mouse-adapted influenza A/Puerto Rico/8/34 virus (PR8) and, 7?days
later, with Streptococcus pneumoniae serotype 3 (Sp3) exhibited significantly
enhanced lung pathology and lethality that was reversed by Eritoran therapy after
PR8 infection but before Sp3 infection. Cotton rats infected with nonadapted
pH1N1 influenza virus and then superinfected with methicillin-resistant
Staphylococcus aureus also exhibited increased lung pathology and serum
high-mobility-group box 1 (HMGB1) levels, both of which were blunted by Eritoran
therapy. In mice, PR8 infection suppressed Sp3-induced CXCL1 and CXCL2 mRNA,
reducing neutrophil infiltration and increasing the bacterial burden, all of
which were reversed by Eritoran treatment. While beta interferon
(IFN-?)-deficient (IFN-?(-/-)) mice are highly susceptible to PR8, they exhibited
delayed death upon Sp3 superinfection, indicating that while IFN-? was protective
against influenza, it negatively impacted the host response to Sp3 IFN-?-treated
WT macrophages selectively suppressed Sp3-induced CXCL1/CXCL2 transcriptionally,
as evidenced by reduced recruitment of RNA polymerase II to the CXCL1 promoter.
Thus, influenza establishes a "trained" state of immunosuppression toward 2°
bacterial infection, in part through the potent induction of IFN-? and its
downstream transcriptional regulation of chemokines, an effect reversed by
Eritoran.IMPORTANCE Enhanced susceptibility to 2° bacterial infections following
infection with influenza virus is a global health concern that accounts for many
hospitalizations and deaths, particularly during pandemics. The complexity of the
impaired host immune response during 2° bacterial infection has been widely
studied. Both type I IFN and neutrophil dysfunction through decreased chemokine
production have been implicated as mechanisms underlying enhanced susceptibility
to 2° bacterial infections. Our findings support the conclusion that selective
suppression of CXCL1/CXCL2 represents an IFN-?-mediated "training" of the
macrophage transcriptional response to TLR2 agonists and that blocking of TLR4
therapeutically with Eritoran after influenza virus infection reverses this
suppression by blunting influenza-induced IFN-?.
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