CHRISTOPHER SUNDLING TEAM

About

Infectious diseases remain one of the largest threats to humanity. The effects of globalisation with rapid mobility and decreasing natural barriers promote the spread of known infectious diseases, resistant pathogens and emerging infectious diseases. However, development of efficacious vaccines and novel biologics continues to be a lengthy and complicated process, emphasising the great need for a better understanding of host-pathogen interactions and the development of protective immunity.

 

Research

Our research focuses on understanding the interplay between different infectious diseases and the immune system. In order to study the immune response after infection we use state-of-the-art technology to investigate the immune system on a cellular, molecular, and genetic level. We then use bioinformatics to analyse the high-dimensional data and combine the results with clinical variables. By comparing several diseases, we can identify unique features associated with the individual pathogens, which in turn can be useful for developing novel diagnostic tests or pin-point potential targets for therapeutics. We also achieve an improved understanding of how the immune system responds to a given infection on a systems scale, which we then further investigate mechanistically.

 

Projects

Defining the immune landscape after acute malaria

Malaria is a complex disease where many cells of both the innate and adaptive immune system are important for disease control. Here we investigate the immune response in a prospective malaria cohort established by Prof. Anna Färnert at the Department of Medicine, KI. Using state-of-the-art methods to analyse the patient samples, we apply bioinformatic tools to integrate parasite-specific antibody data, cell phenotyping, plasma profiling for inflammatory markers, and clinical data to obtain a more complete picture of how the immune system responds during acute malaria and potential implication for clinical presentation and long-term immunity (Figure 1).

 

Differentiation and function of atypical B cells

We could previously show that atypical B cells are greatly expanded during and briefly after acute malaria and that these cells then slowly contract over time (Sundling et al. JCI Insight, 2019). However, the specific cues for B cells to differentiate to atypical cells and their function in vivo remains unclear and several studies have suggested that they are a dysfunctional memory cell subset. This is especially relevant in malaria as immunity is slow to build and rapidly decline in the absence of exposure or following vaccination. In this project we investigate atypical B cell differentiation in vitro under different combinations of stimulants mimicking the in vivo situation during malaria. We further go on to evaluate atypical B cell function of the in vitro derived cells and compare with ex vivo sorted atypical B cells.

 

Impact of the IgG3 hinge on atypical B cell expansion

The atypical B cells are greatly enriched for cells using an IgG1 or IgG3 constant domain. This has been attributed to the Th1-skewed immune response elicited during chronic viral infection or malaria. IgG1 is commonly expressed by switched memory B cells (~85% of IgG-switched cells), however, IgG3 is very rare (~1% of IgG-switched cells). Atypical B cells, however, can be enriched >20-fold for IgG3+ B cells, strongly suggesting either efficient switching from previously unswitched cells or a preferential expansion of IgG3+ B cells. In previous work we have shown that B cells with an extended hinge has a strong selection advantage during germinal centre selection (Sundling et al., Immunity. 2021). In this project we will investigate the contribution of this mechanism to atypical B cell expansion in vivo, using a hen-egg lysozyme B cell receptor knock-in mouse model.

 

Identification of unique immune signatures in different infectious diseases

Pathogens use highly specialised methods to infect their host. This leads to an equally specific response by the host immune system. In this project we take advantage of this specificity to investigate if we can distinguish different pathogens from each other based on the immune profile generated during acute infection. We then further correlate the immune signature with clinical outcomes, to determine if we can identify biomarkers associated with disease severity. This study is primarily performed in a cohort consisting of individuals seeking health care due to developing fever after travel to tropical- or subtropical areas. As fever is a common, non-specific symptom the cohort includes a wide variety of pathogens. The most common ones include malaria parasites, dengue virus, influenza virus and enteric bacteria, however, in approximately 50% of cases, no aetiological agent is determined. By identifying immune signatures associated with specific pathogens and disease severity, we hope to improve on current commonly used biomarkers, such as C-reactive protein and procalcitonin.

 

Novel biomarkers for improved identification of TB disease progression

It is estimated that approximately one quarter of the world’s population has been infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). However, only a fraction of these develop active disease. With the exception of obvious risk groups, such as HIV infection, immunosuppression, and pregnancy, it remains unclear why some individuals develop active disease, while some individuals manage to control or clear the infection. By investigating cytokine/chemokine signatures and perform cell profiling of individuals with active or controlled infection, we aim to improve our understanding understanding of this process. This will be important, both for development of improved screening tests, but also to understand which immune responses are needed to suppress or clear the infection, which in turn will be helpful for vaccine design.

 

Collaborators

Karolinska Institutet and Karolinska University Hospital

Anna Färnert

Anna Smed-Sörensen

Klara Sondén

Judith Bruchfeld

Gunilla Källenius

Nadir Kadri

 

Umeå University

Mattias Forsell

Clas Alm

 

University of Minho, Portugal

Margarida Correia-Neves

 

Garvan Institute of Medical Research

Robert Brink

 

Grants

Svenska läkaresällskapet, 2020

Sigurd och Elsa Goljes Minne, 2020

Clas Groschinskys Minnesfond, 2020-2021

Vetenskapsrådet starting grant, 2020-2023

Åke Wiberg Foundation, 2018 and 2019

Magnus Bergvall Foundation, 2017, 2018, 2019

Tore Nilsson Foundation, 2018

 

Selected publications

Positive selection of IgG+ over IgM+ B cells in the germinal center reaction.
Sundling C, Lau AWY, Bourne K, Young C, Laurianto C, Hermes JR, Menzies RJ, Butt D, Kräutler NJ, Zahra D, Suan D, Brink R
Immunity 2021 Apr;():

Memory B-Cell Responses Against Merozoite Antigens After Acute Plasmodium falciparum Malaria, Assessed Over One Year Using a Novel Multiplexed FluoroSpot Assay.
Jahnmatz P, Sundling C, Yman V, Widman L, Asghar M, Sondén K, Stenström C, Smedman C, Ndungu F, Ahlborg N, Färnert A
Front Immunol 2020 ;11():619398

Stabilization of blood for long-term storage can affect antibody-based recognition of cell surface markers.
Silva MH, Lepzien R, Ols S, Dahlberg B, Grunewald J, Loré K, et al
J. Immunol. Methods 2020 May;():112792

Multiplex analysis of antigen-specific memory B cells in humans using reversed B-cell FluoroSpot.
Jahnmatz P, Sundling C, Makower B, Sondén K, Färnert A, Ahlborg N
J. Immunol. Methods 2020 Mar;478():112715

B cell profiling in malaria reveals expansion and remodelling of CD11c+ B cell subsets.
Sundling C, Rönnberg C, Yman V, Asghar M, Jahnmatz P, Lakshmikanth T, et al
JCI Insight 2019 Apr;5():

Immunization-Elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability.
Zhao X, Howell KA, He S, Brannan JM, Wec AZ, Davidson E, et al
Cell 2017 May;169(5):891-904.e15

Antibody responses to merozoite antigens after natural Plasmodium falciparum infection: kinetics and longevity in absence of re-exposure.
Yman V, White MT, Asghar M, Sundling C, Sondén K, Draper SJ, et al
BMC Med 2019 01;17(1):22

Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells.
Kräutler NJ, Suan D, Butt D, Bourne K, Hermes JR, Chan TD, et al
J. Exp. Med. 2017 05;214(5):1259-1267

Plasma cell and memory B cell differentiation from the germinal center.
Suan D, Sundling C, Brink R
Curr. Opin. Immunol. 2017 Apr;45():97-102

Single-cell and deep sequencing of IgG-switched macaque B cells reveal a diverse Ig repertoire following immunization.
Sundling C, Zhang Z, Phad GE, Sheng Z, Wang Y, Mascola JR, et al
J. Immunol. 2014 Apr;192(8):3637-44

High-resolution definition of vaccine-elicited B cell responses against the HIV primary receptor binding site.
Sundling C, Li Y, Huynh N, Poulsen C, Wilson R, O'Dell S, et al
Sci Transl Med 2012 Jul;4(142):142ra96

Isolation of antibody V(D)J sequences from single cell sorted rhesus macaque B cells.
Sundling C, Phad G, Douagi I, Navis M, Karlsson Hedestam GB
J. Immunol. Methods 2012 Dec;386(1-2):85-93

Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates.
Sundling C, Forsell MN, O'Dell S, Feng Y, Chakrabarti B, Rao SS, et al
J. Exp. Med. 2010 Aug;207(9):2003-17

High-Resolution Longitudinal Study of HIV-1 Env Vaccine-Elicited B Cell Responses to the Virus Primary Receptor Binding Site Reveals Affinity Maturation and Clonal Persistence.
Wang Y, Sundling C, Wilson R, O'Dell S, Chen Y, Dai K, et al

J. Immunol. 2016 05;196(9):3729-43