Stephanie L. Silva-Del Toro
University of Iowa
Iowa City, IA
Mechanisms of H. Pylori-Induced Neutrophil Nuclear Hypersegmentation
Stephanie L. Silva-Del Toro*, University of Iowa and Lee-Ann Allen, University of Iowa Inﬂammation Program
Helicobacter pylori is a human pathogen that resides in the gastric mucosa, eliciting a neutrophil (PMN) dominant inﬂammatory response that can progress to peptic ulcer disease or gastric cancer. PMNs exhibit signiﬁcant functional and phenotypic plasticity, and we recently demonstrated that these cells undergo N1-like-subtype diﬀerentiation in-vitro following H. pylori infection. This phenotype is notable for profound nuclear hypersegmentation and a proinﬂammatory and cytotoxic phenotype. Our objective is to deﬁne the underlying mechanisms with a focus on nuclear hypersegmentation. We have shown that direct infection and both host and bacterial transcription and protein synthesis are essential. Recent studies using nocodazole and taxol identiﬁed an additional requirement for microtubule
(MT) dynamics. Moreover, STED-super-resolution microscopy analysis showed that MTs are longer and more abundant following H. pylori infection. Inhibition by Brefeldin A and Exo1 suggested an additional role for anterograde transport, and to our surprise revealed unexpected eﬀects of Brefeldin A on PMN microtubule dynamics. Finally, we used antibodies against lamin B receptor and STED-super-resolution microscopy imagining to analyze PMN nuclei in unprecedented detail. These data demonstrate that the volume of the H. pylori infected PMN nucleus is signiﬁcantly increased and the PMN nuclear volume is altered when cells were treated with MT disruptors. The uniformity of distribution of lamin B receptor in the nuclear membrane was also evaluated and it is altered by drugs that manipulate MT dynamics. Altogether, our data provide fundamental insight into the mechanisms that regulate PMN nuclear morphology as well as the consequences of H. pylori infection.
Honolulu, October 31 - November 2, 2019
- Emmons, TR, Giridharan, T, Singel, KL, Khan, ANH, Ricciuti, J, Howard, K, Silva-Del Toro, SL, Debreceni, IL, Aarts, CEM, Brouwer, MC et al.. Mechanisms Driving Neutrophil-Induced T-cell Immunoparalysis in Ovarian Cancer. Cancer Immunol Res 2021; 9 (7): 790-810. PubMed PMID:33990375 PubMed Central PMC8287091.
- Silva-Del Toro, SL, Allen, LH. Microtubules and Dynein Regulate Human Neutrophil Nuclear Volume and Hypersegmentation During H. pylori Infection. Front Immunol 2021; 12 : 653100. PubMed PMID:33828562 PubMed Central PMC8019731.
- Silva-Del Toro, SL, Greenwood-Quaintance, KE, Patel, R. In vitro activity of tedizolid against linezolid-resistant staphylococci and enterococci. Diagn Microbiol Infect Dis 2016; 85 (1): 102-4. PubMed PMID:26971179 PubMed Central PMC8067670.