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Immunity to Rotavirus infection across ages

Muleta, Konjit Getachew LU (2022) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Rotavirus (RV) is a double-stranded RNA virus that mainly affects young children under the age of five years. It is one of the leading causes of dehydrating gastroenteritis. Every year, about 200,000 child deaths occur due to RV
infection. Vaccines exist and are in use worldwide. However, these vaccines' efficacy is relatively low in countries where deaths due to the virus are high.
The aim of the work presented in this thesis was to understand the requirements for RV-specific adaptive immunity in both adult and neonatal settings.
In paper I, we showed that innate signalling molecules, namely MyD88 and
TLR3, were not required individually and that their genetic depletion did not impact on the priming of RV-specific CD8+ T... (More)
Rotavirus (RV) is a double-stranded RNA virus that mainly affects young children under the age of five years. It is one of the leading causes of dehydrating gastroenteritis. Every year, about 200,000 child deaths occur due to RV
infection. Vaccines exist and are in use worldwide. However, these vaccines' efficacy is relatively low in countries where deaths due to the virus are high.
The aim of the work presented in this thesis was to understand the requirements for RV-specific adaptive immunity in both adult and neonatal settings.
In paper I, we showed that innate signalling molecules, namely MyD88 and
TLR3, were not required individually and that their genetic depletion did not impact on the priming of RV-specific CD8+ T cell responses. Likewise, the priming of RV-specific CD8+ T cells remained unaffected in IFNAR deficient
mice. The ability of RV-specific CD8+ T cells to produce IFNγ and granzyme, however, was blunted in the absence of IFNAR signaling. This shows the redundant function of innate signaling molecules in inducing RV-specific CD8+
T cell responses in an adult setting.
In Paper II and III, we assessed the requirements for the B cell antibody response during RV infection in both adult and neonatal mice, respectively. We showed that BATF3-dependent cDC1 are required for the initiation of optimal
B cell responses across ages. The context of their requirement however differs between neonates and adults. In adults, BATF3-dependent cDC1 are primarily required for the class switching to IgA plasmablasts, also impacting to some extent on the accumulation of total plasmablasts. The IgA induction partially depends on the selective expression of the TGFβ activating integrin, αvβ8, on cDC1. On the other hand, in the neonates, cDC1 are required for the general accumulation of plasmablasts but not for IgA class switching, suggesting that the mechanism of cDC-induced B cell induction and isotype switching may differ across ages.
In paper IV, we investigated the impact of preconception RV infection and its consequence on the immunity to RV infection of their offspring. We show that RV-infected pups born to RV-immune dams received high levels of RV-specific
antibodies through breast milk and were protected from RV-induced pathology. However, they immunologically respond to the virus as assessed by accumulation of GC B cells and plasmablasts in their mLN. This accumulation of GC B cells and plasmablasts in RV-infected pups born to RV-immune dams does not translate into the induction of RV-specific IgA responses towards the RV immunodominant epitope (VP6) as compared to RV-infected pups born to naïve dams that mounted high level of VP6-specific IgA. Nevertheless, RV-infected pups born to RV-immune dams are equally protected from reinfection later in life regardless of the lack of VP6-specific antibodies in pups born to RV-immune dams. This suggests that, in the presence of the mother-derived RV-specific
antibodies, the pups respond using a different yet protective B cell repertoire.
Collectively, the work included in this thesis broadens our current understanding of immunity to RV infection across ages, hopefully contributing to the design of better vaccines able to provide protection in countries where the efficacy of the current vaccine is relatively low. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Associate Professor Westerberg, Lisa, Karolinska Institute, Stockholm, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Rotavirus, B cells, T cells, Dendritic cells, Mesenteric Lymph Node, CD8 T cells, Maternal protection, IgA, Neonates, Small Inestinal lamina propria, IFNAR signaling
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2022:121
pages
62 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/69461196020?pwd=Q1Brakt4NVVpSHo3dTA1bW9zNUR0UT09
defense date
2022-09-15 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-283-0
language
English
LU publication?
yes
id
e9fe0676-ab41-4c9c-8522-758756808a1c
date added to LUP
2022-08-16 10:07:31
date last changed
2022-08-31 09:01:05
@phdthesis{e9fe0676-ab41-4c9c-8522-758756808a1c,
  abstract     = {{Rotavirus (RV) is a double-stranded RNA virus that mainly affects young children under the age of five years. It is one of the leading causes of dehydrating gastroenteritis. Every year, about 200,000 child deaths occur due to RV<br/>infection. Vaccines exist and are in use worldwide. However, these vaccines' efficacy is relatively low in countries where deaths due to the virus are high.<br/>The aim of the work presented in this thesis was to understand the requirements for RV-specific adaptive immunity in both adult and neonatal settings.<br/>In paper I, we showed that innate signalling molecules, namely MyD88 and<br/>TLR3, were not required individually and that their genetic depletion did not impact on the priming of RV-specific CD8+ T cell responses. Likewise, the priming of RV-specific CD8+ T cells remained unaffected in IFNAR deficient<br/>mice. The ability of RV-specific CD8+ T cells to produce IFNγ and granzyme, however, was blunted in the absence of IFNAR signaling. This shows the redundant function of innate signaling molecules in inducing RV-specific CD8+<br/>T cell responses in an adult setting.<br/>In Paper II and III, we assessed the requirements for the B cell antibody response during RV infection in both adult and neonatal mice, respectively. We showed that BATF3-dependent cDC1 are required for the initiation of optimal<br/>B cell responses across ages. The context of their requirement however differs between neonates and adults. In adults, BATF3-dependent cDC1 are primarily required for the class switching to IgA plasmablasts, also impacting to some extent on the accumulation of total plasmablasts. The IgA induction partially depends on the selective expression of the TGFβ activating integrin, αvβ8, on cDC1. On the other hand, in the neonates, cDC1 are required for the general accumulation of plasmablasts but not for IgA class switching, suggesting that the mechanism of cDC-induced B cell induction and isotype switching may differ across ages.<br/>In paper IV, we investigated the impact of preconception RV infection and its consequence on the immunity to RV infection of their offspring. We show that RV-infected pups born to RV-immune dams received high levels of RV-specific<br/>antibodies through breast milk and were protected from RV-induced pathology. However, they immunologically respond to the virus as assessed by accumulation of GC B cells and plasmablasts in their mLN. This accumulation of GC B cells and plasmablasts in RV-infected pups born to RV-immune dams does not translate into the induction of RV-specific IgA responses towards the RV immunodominant epitope (VP6) as compared to RV-infected pups born to naïve dams that mounted high level of VP6-specific IgA. Nevertheless, RV-infected pups born to RV-immune dams are equally protected from reinfection later in life regardless of the lack of VP6-specific antibodies in pups born to RV-immune dams. This suggests that, in the presence of the mother-derived RV-specific<br/>antibodies, the pups respond using a different yet protective B cell repertoire.<br/>Collectively, the work included in this thesis broadens our current understanding of immunity to RV infection across ages, hopefully contributing to the design of better vaccines able to provide protection in countries where the efficacy of the current vaccine is relatively low.}},
  author       = {{Muleta, Konjit Getachew}},
  isbn         = {{978-91-8021-283-0}},
  issn         = {{1652-8220}},
  keywords     = {{Rotavirus; B cells; T cells; Dendritic cells; Mesenteric Lymph Node; CD8 T cells; Maternal protection; IgA; Neonates; Small Inestinal lamina propria; IFNAR signaling}},
  language     = {{eng}},
  number       = {{2022:121}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Immunity to Rotavirus infection across ages}},
  url          = {{https://lup.lub.lu.se/search/files/122698842/e_spik_ex_kanjit.pdf}},
  year         = {{2022}},
}