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In vivo dynamics of antibody responses to lymph-borne viruses

Final Report Summary - IVM-VIRUS-NAB (In vivo dynamics of antibody responses to lymph-borne viruses)

Antibodies are critical for virus control, prevention of re-infection and protection conferred by available vaccines. Thanks to the recent advent of multiphoton intravital microscopy, several cellular and molecular events by which lymph nodes orchestrate the generation of humoral immune responses have been clarified. As none of these studies employed live viruses, this project aimed to extend these results to a more relevant natural setting. Also, the mechanisms by which acutely cytopathic viruses (e.g. polioviruses and rabies virus in humans and vesicular stomatitis virus [VSV] in mice) induce early high affinity nAb responses while non-cytopathic viruses (e.g. hepatitis B virus or hepatitis C virus in humans and lymphocytic choriomeningitis virus [LCMV] in mice) fail to do so remain poorly understood. By bringing together unique reagents and advanced technology, this project was able to address these issues experimentally.

Specifically, the most noteworthy scientific and technological achievements of this project have been:

1) The identification of inflammatory monocytes as critical gatekeepers that restrain antiviral B cell responses. Our results suggest that certain viruses take advantage of these cells to prolong their persistence within the host (Sammicheli, Kuka et al., Science Immunology 2016). These results have received significant coverage, including a Focus article in Science Immunology and a Research Highlight from Nature Reviews Immunology. Based on this publication, we have been asked by Nature Reviews Immunology to write a review article (Kuka and Iannacone, Viral subversion of B cell responses, Nature Reviews Immunology, in press).

2) The discovery that bisphosphonates, drugs that are widely used to inhibit loss of bone mass in patients, have a potent adjuvant effect that boost humoral immune responses (Tonti et al., Cell Reports 2013 and Vaccines Comprising Bisphosphonates and Methods of Use Thereof, United States Patent Application 20130309270). Translational evaluation of these compounds in humans should be relatively straightforward, because bisphosphonates, unlike all other adjuvants, are already widely used in the clinic as stand-alone drugs with excellent safety profiles. Thus, bisphosphonates could be readily combined with both existing and newly developed vaccines, especially in settings where immune responses to a vaccine alone are weak or where antigens are in short supply.

3) The implementation of novel platforms for advanced imaging, most notably a correlative light and electron microscopy technique applied to liver tissue (Guidotti, Inverso et al., Cell 2015).

4) The establishment of a novel technology for the spatial reconstruction of immune niches by combining photoactivatable fluorescent reporter and single-cell RNA-seq. This manuscript has received very good reviews from Science and we are in the process of revising it for resubmission by the end of September 2017.

5) The generation of novel viruses and mouse models for the study of antiviral humoral immune responses that will be useful to us and to other academic or industrial researchers (Sammicheli, Kuka et al., Science Immunology 2016)


Guidotti LG*, Inverso D*, Sironi L, Di Lucia P, Fioravanti J, Fiocchi A, Vacca M, Aiolfi R, Sammicheli S, Mainetti M, Ganzer L, Cataudella T, Raimondi A, Gonzalez-Aseguinolaza G, Protzer U, Ruggeri ZM, Chisari FV, Isogawa M, Sitia G, Iannacone M (2015) Immunosurveillance of the liver by intravascular effector CD8+ T cells. Cell, 161:486 (*co-first authors)

Kuka M and Iannacone M (2018) Viral subversion of B cell responses. Nature Reviews Immunology, in press

Sammicheli S*, Kuka M*, Di Lucia P, Jimenez de Oya N, De Giovanni M, Fioravanti J, Cristofani C, Maganuco CG, Fallet B, Ganzer L, Sironi L, Mainetti M, Ostuni R, Larimore K, Greenberg PD, de la Torre JC, Guidotti LG, Iannacone M (2016) Inflammatory monocytes hinder antiviral B cell responses. Science Immunology, 1:eaah6789 (*co-first authors)

Tonti E, Jimenez de Oya N, Galliverti G, Moseman EA, Di Lucia P, Amabile A, Sammicheli S, De Giovanni M, Sironi L, Chevrier N, Sitia G, Gennari L, Guidotti LG, von Andrian UH, Iannacone M (2013) Bisphosphonates target B cells to enhance humoral immune responses. Cell Reports, 5:323