Staphylococcus aureus Infection and Persistence in Chronic Rhinosinusitis: Focus on Leukocidin ED

Chronic rhinosinusitis (CRS) is thought to be a multifactorial disease that includes a direct involvement of bacteria that trigger inflammation and contribute to CRS pathogenesis. Staphylococcus aureus infection and persistence is associated with chronic rhinosinusitis (CRS), and it may be particularly relevant in the form with nasal polyps (CRSwNP). The large array of exotoxins deployed by S. aureus is instrumental for the bacterium to warrant its infection and dissemination in different human body districts. Here, we analyze the common Th2 environment in CRSwNP and prospect a possible dynamic role played by S. aureus leukocidins in promoting this chronic inflammation, considering leukocidin ED (LukED) as a strong prototype candidate worth of therapeutic investigation. CCR5 is an essential target for LukED to exert its cytotoxicity towards T cells, macrophages and dendritic cells. Therefore, CCR5 blockade might be an interesting therapeutic option for CRS and, more specifically, persistent and relapsing CRSwNP. In this perspective, the arsenal of CCR5 antagonists being developed to inhibit HIV-1 entry (CCR5 being the major HIV-1 co-receptor) could be easily repurposed for CRS therapeutic investigation. Finally, direct targeting of LukED by neutralizing antibodies could represent an important additional solution to S. aureus infection.

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Observational study of skin and soft-tissue Staphylococcus aureus infection in patients infected with HIV-1 and epidemics of Panton–Valentine leucocidin-positive community-acquired MRSA infection in Osaka, Japan

Journal of Infection and Chemotherapy ◽

10.1016/j.jiac.2020.07.007 ◽

2020 ◽

Vol 26 (12) ◽

pp. 1254-1259

Author(s):

Kazuyuki Hirota ◽

Dai Watanabe ◽

Yusuke Koizumi ◽

Daisuke Sakanashi ◽

Takashi Ueji ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Soft Tissue ◽

Observational Study ◽

Aureus Infection ◽

Mrsa Infection ◽

Hiv 1

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Alterations in the Immunogenic Properties of Soluble Trimeric Human Immunodeficiency Virus Type 1 Envelope Proteins Induced by Deletion or Heterologous Substitutions of the V1 Loop

Journal of Virology ◽

10.1128/jvi.00868-10 ◽

2010 ◽

Vol 84 (19) ◽

pp. 9932-9946 ◽

Cited By ~ 11

Author(s):

Lance Ching ◽

Leonidas Stamatatos

Keyword(s):

Neutralizing Antibodies ◽

Hypervariable Region ◽

Immunodeficiency Virus ◽

Cd4 Binding Site ◽

Gp140 Envelope ◽

The Common ◽

Immunogenic Properties ◽

Hiv 1 ◽

High Immunogenicity

ABSTRACT HIV-1 gp140 envelope immunogens express conserved epitopes that are targeted by broadly cross-reactive neutralizing antibodies, but they fail to elicit similar antibodies upon immunization. The poor immunogenicity of conserved epitopes on gp140 could be linked to the high immunogenicity of variable Env regions on such constructs. Previous studies have shown that the first hypervariable region (V1 loop) is immunogenic on soluble gp140s but elicits type-specific antibodies. To address issues related to the high immunogenicity of the V1 loop, two conceptually opposite approaches were tested. In the first approach, we eliminated the V1 loop from our gp140 construct and examined how V1 deletion altered the immunogenic properties of other Env regions. In the second approach, we took advantage of the high immunogenicity of the V1 loop and engrafted four diverse V1 loops onto a common gp140 Env “scaffold.” These four scaffolds were used as a cocktail of immunogens to elicit diverse anti-V1 antibodies, under the hypothesis that eliciting diverse anti-V1 antibodies would expand the neutralizing breadth of immune sera. Our study indicates that three of four heterologous V1 loops were immunogenic on the common Env backbone “scaffold,” but heterologous anti-V1 neutralizing responses were observed in only one case. Both types of V1 modification dampened the immunogenicity of the V3 loop, differentially altered the immunogenicity of the transmembrane gp41 subunit, and altered the relative immunogenicities of unknown Env regions, including potentially the CD4-binding site (CD4-bs) and trimer-specific targets, which elicited cross-reactive neutralizing antibodies but of limited breadth.

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