Streptococcus agalactiae cadD alleviates metal stress and promotes intracellular survival in macrophages and ascending infection during pregnancy

Michelle L. Korir, Ryan S. Doster, Jacky Lu, Miriam A. Guevara, Sabrina K. Spicer, Rebecca E. Moore, Jamisha D. Francis, Lisa M. Rogers, Kathryn P. Haley, Amondrea Blackman, Kristen N. Noble, Alison J. Eastman, Janice A. Williams, Steven M. Damo, Kelli L. Boyd, Steven D. Townsend, C. Henrique Serezani, David M. Aronoff, Shannon D. Manning () and Jennifer A. Gaddy ()
Additional contact information
Michelle L. Korir: Michigan State University, Department of Microbiology and Molecular Genetics
Ryan S. Doster: Vanderbilt University Medical Center
Jacky Lu: Vanderbilt University Medical Center
Miriam A. Guevara: Vanderbilt University Medical Center
Sabrina K. Spicer: Vanderbilt University
Rebecca E. Moore: Vanderbilt University Medical Center
Jamisha D. Francis: Vanderbilt University Medical Center
Lisa M. Rogers: Vanderbilt University Medical Center
Kathryn P. Haley: Vanderbilt University Medical Center
Amondrea Blackman: Vanderbilt University Medical Center
Kristen N. Noble: Vanderbilt University Medical Center
Alison J. Eastman: Vanderbilt University Medical Center
Janice A. Williams: United States Army Medical Research Institute of Infectious Diseases
Steven M. Damo: Fisk University
Kelli L. Boyd: Vanderbilt University Medical Center
Steven D. Townsend: Vanderbilt University
C. Henrique Serezani: Vanderbilt University Medical Center
David M. Aronoff: Vanderbilt University Medical Center
Shannon D. Manning: Michigan State University, Department of Microbiology and Molecular Genetics
Jennifer A. Gaddy: Vanderbilt University Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Perinatal infection with Streptococcus agalactiae, or Group B Streptococcus (GBS), is associated with preterm birth, neonatal sepsis, and stillbirth. Here, we study the interactions of GBS with macrophages, essential sentinel immune cells that defend the gravid reproductive tract. Transcriptional analyses of GBS-macrophage co-cultures reveal enhanced expression of a gene encoding a putative metal resistance determinant, cadD. Deletion of cadD reduces GBS survival in macrophages, metal efflux, and resistance to metal toxicity. In a mouse model of ascending infection during pregnancy, the ΔcadD strain displays attenuated bacterial burden, inflammation, and cytokine production in gestational tissues. Furthermore, depletion of host macrophages alters cytokine expression and decreases GBS invasion in a cadD-dependent fashion. Our results indicate that GBS cadD plays an important role in metal detoxification, which promotes immune evasion and bacterial proliferation in the pregnant host.

Date: 2022
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DOI: 10.1038/s41467-022-32916-7

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