Stimulation via Toll‐like receptor 9 reduces Cryptococcus neoformans‐induced pulmonary inflammation in an IL‐12‐dependent manner

Abstract

Cytosine‐phosphate‐guanosine‐containing oligodeoxynucleotides (CpG ODN) are important vaccine adjuvants that promote Th1‐type immune responses. Cryptococcus neoformans is a serious human pathogen that replicates in the lung but may disseminate systemically leading to meningitis, particularly in immunocompromised individuals. Immunization of susceptible C57BL/6 mice with CpG ODN deviates the immune response from a Th2‐ toward a Th1‐type response following infection with C. neoformans. CpG also induces IL‐12, TNF, MCP‐1 and macrophage nitric oxide production. CD4+ and CD8+ T cells producing IFN‐γ increase in frequency, while those producing IL‐5 decrease. More importantly, pulmonary eosinophilia is significantly reduced, an effect that depends on IL‐12 and CD8+ T cells but not NK cells. CpG treatment also reduces the burden of C. neoformans in the lung, an effect that is IL‐12‐, NK cell‐ and T cell‐independent and probably reflects a direct effect of CpG on pathogen opsonization or an enhancement of macrophage antimicrobial activity. An equivalent beneficial effect is also observed when CpG ODN treatment is delivered during established cryptococcal disease. This is the first study documenting that promotion of lung TLR9 signaling using synthetic agonists enhances host defense. Activation of innate immunity has clear therapeutic potential and may even be beneficial in patients with acquired immune deficiency.

TLR9 activation is a key event for the maintenance of a mycobacterial antigen‐elicited pulmonary granulomatous response

“…TLR9 recognizes as ligands viral and bacterial CpG-DNA motifs, which when bound to TLR9 on macrophages and DC, causes their activation [38][39][40]. A number of studies indicate that CpG-DNA TLR9 interaction can drive a Th1 immune response, as evidenced by a Th1-dominated cytokine profile [41][42][43]. A recent report demonstrated that TLR9 played an important role in the regulation of the mycobacteriainduced Th1 responses during M. tuberculosis infection in vivo [44].…”

TLR9 Signaling Is Required for Generation of the Adaptive Immune Protection in Cryptococcus neoformans-Infected Lungs

“…Previous studies indicated that TLR9 contributes to anticryptococcal host defenses. [52][53][54] Synthetic CpGDNA co-administered during C. neoformans infection enhances the development of Th1 response and reduces C. neoformans burden. 54 In addition, cooperative stimulation of DC by cryptococcal mannoproteins and CpG OligodN was demonstrated in vitro.…”

“…[52][53][54] Synthetic CpGDNA co-administered during C. neoformans infection enhances the development of Th1 response and reduces C. neoformans burden. 54 In addition, cooperative stimulation of DC by cryptococcal mannoproteins and CpG OligodN was demonstrated in vitro. 53 Cryptococcal DNA and cell lysates have been shown to activate dendritic cell maturation and to induce IL-12 (pro-Th1 cytokine) production via TLR9 mediated mechanism in vitro.…”

The Acquired Immune Response to the Mucosal Adjuvant LTK63 Imprints the Mouse Lung with a Protective Signature

“…In addition to vaccination, protection of the mucosal surfaces can be elicited by several non-antigenic immune-stimulatory compounds; however, little is known about the molecular and cellular mechanisms associated with such generic protection (4,19,20). Pulmonary administration of CpG to the mouse lung protects from Cryptococcus neoformans challenge in an IL12-dependent manner (20).…”

“…Pulmonary administration of CpG to the mouse lung protects from Cryptococcus neoformans challenge in an IL12-dependent manner (20). Similarly, up to 2 wk following the pulmonary administration of LTK63 mice are resistant to infections with respiratory syncytial virus (RSV), influenza virus, or C. neoformans.…”