Team Lennart Svensson
Susceptibility and Disease Mechanisms to Rotavirus and Norovirus Infections
Rotavirus and norovirus (the winter vomiting disease, “vinterkräksjuka”) are major causes of acute diarrhea worldwide, with a burden of >500,000 deaths per year, predominantly in developing countries. While the clinical importance of these infections is significant and a vaccine against rotavirus has been introduced globally, the underlying disease mechanisms are still unresolved.
Our research on rotavirus and norovirus is hypothesis driven and translational. Currently, we investigate the cross-talk between enterochromaffin cells, enteric glia cells, enteric nerves and CNS during rotavirus and norovirus infections and how infection activates brain structures associated with the feeling of sickness. We also investigate human genetic factors associated with rotavirus and norovirus susceptibility, to explain why certain individuals get sick and not others when exposed.
Current projects at a glance
Does the vagal nerve and/or enteric glial cells contribute to maintaining a tight intestinal epithelium during rotavirus infection?
We have previously shown that intestinal permeability remains unaffected during rotavirus infection in children and mice, which is in contrast with increased intestinal permeability during bacterial infections. Since intestinal permeability is partially regulated by the vagus nerve and neurotrophic factors released from enteric glial cells, we propose that vagus and/or enteric glial cells contribute to maintaining a tight intestinal epithelium during rotavirus infection. These studies may uncover how the gut epithelium remains intact during rotavirus infection in human and mice.
Human enteroids: A novel cultivation model for human norovirus.
The major barrier to research and development of effective interventions for human norovirus infections has been the lack of a robust and reproducible in vitro cultivation system and a small animal model. A major advance in this field was recently described by Ettayebi et al (Science 2016), who reported successful cultivation of multiple human norovirus strains in enterocytes of stem cell–derived enteroid cultures. The enteroids are produced from small intestinal biopsies donated by consenting individuals and contain stem-cells that developed/derived into multiple intestinal epithelial cell types including enterocytes, goblet cells, enterochromaffin- and Paneth cells. This non-transformed culture system recapitulates the human intestinal epithelium, permits human host-pathogen studies of previously non-cultivatable pathogens, and allows the assessment of methods to prevent and treat human norovirus infections. The method is established in my group and explored for several kind of experiments such as determination of norovirus infectivity in clinical specimens, co-culturing of enteroids with enteric nerves and/or enteric glia cells.
Human enteroids to identify restriction factors to rotavirus and norovirus infection
Human gut-virus studies have been hampered by use of sub-optimal in vitro intestinal cell models, mainly transformed cells. In this project we take advantage of the non-transformed human enteroid model to identify the cellular receptor for rotavirus and norovirus and to identify restriction factors limiting infections of certain types of rotavirus in certain geographic regions. Our hypothesis is that polymorphisms in secretor- and Lewis antigens restrict certain rotavirus infections. To address this question, we take advantage of the library of human enteroids that we have built from patients with different genetic set up.
Are there individual-specific responses in the gut to rotavirus and norovirus?
Historically virus-host interactions have been investigated using different pathogens on transformed cell cultures. This (may) answer the question how different pathogens interact on the same cells, but do not answer if the host responses to a single pathogen is unique to each individual. To address this question, we investigate the innate response of a single virus specimen to differentiated enteroid cultures obtained from 10-12 individuals with different polymorphisms with respect to FUT2 and FUT3, genes encoding secretor- and Lewis antigens respectively.
Does rotavirus activate brain structures associated with sickness feeling?
Rotavirus infection includes sickness feeling such as nausea, fever, loss of appetite and social withdrawn. The mechanism and signaling pathways underlying these symptoms is unresolved. A novel objective is to identify the activated regions in the CNS following rotavirus infection, giving raise to sickness feeling. We have previously shown that rotavirus activate the enteric nervous system (Lundgren et al, Science, 2000) and the vomiting center (Hagbom et al, PLoS Path, 2011) and those studies are the basis for our further investigations. Our working hypothesis is that rotavirus infection of the small intestine activates regions within hypothalamus and/or dorsal motor nucleus via the vagus nerve.
Will gastrointestinal viral infection affect telomere length and the biological clock?
Virus infection can induce various cellular remodeling events and stress responses, including telomere-specific alterations. While previous studies have shown that viral infection in the gastrointestinal tract accelerate differentiation of crypt cells towards mature enterocytes, no information is available if teleomere length and thus life span and the biological clock is affected. In a collaboration with Asghar Huhammad and Anna Färnert, we investigate if acute infection with rotavirus and norovirus accelerate aging by shorting the telomere length.
Members of the group
Genetic Susceptibility to Human Norovirus Infection: An Update.
Nordgren J, Svensson L
Viruses 2019 03;11(3):
Crawford SE, Ramani S, Tate JE, Parashar UD, Svensson L, Hagbom M, et al
Nat Rev Dis Primers 2017 Nov;3():17083
Human Sera Collected between 1979 and 2010 Possess Blocking-Antibody Titers to Pandemic GII.4 Noroviruses Isolated over Three Decades.
Sharma S, Carlsson B, Czakó R, Vene S, Haglund M, Ludvigsson J, et al
J. Virol. 2017 07;91(14):
Innate Resistance and Susceptibility to Norovirus Infection.
Nordgren J, Sharma S, Kambhampati A, Lopman B, Svensson L
PLoS Pathog. 2016 04;12(4):e1005385
Role of the enteric nervous system in the fluid and electrolyte secretion of rotavirus diarrhea.
Lundgren O, Peregrin AT, Persson K, Kordasti S, Uhnoo I, Svensson L
Science 2000 Jan;287(5452):491-5
Rotavirus stimulates release of serotonin (5-HT) from human enterochromaffin cells and activates brain structures involved in nausea and vomiting.
Hagbom M, Istrate C, Engblom D, Karlsson T, Rodriguez-Diaz J, Buesa J, et al
PLoS Pathog. 2011 Jul;7(7):e1002115