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IgM in the regulation of TB immunity

Award Number: R01AI139297
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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IgM in the regulation of TB immunity - Abstract A role for T cells in the control of Mycobacterium tuberculosis (Mtb) is well established, that for B cells and humoral immunity, however, is less well understood. Emerging evidence indicate B cells and immunoglobulins (Igs) can modulate the immune response to Mtb in hosts such as humans, non-human primates (NHP), and mice. In humans, antibodies (Ab) has been shown to modulate disease outcome and/or confer protection. We have shown that S-/- mice, which lack secreted IgM, are more susceptible to Mtb compared to wild-type (WT) C57BL/6. The susceptibility phenotype manifests as enhanced mortality and tissue bacterial loads in the chronic phase of infection. S-/- mice also exhibit germinal center (GC) defects characterized by histological abnormality, decreased levels of plasma cells/plasmablasts, and an impaired GC B cell and antigen (Ag)- specific IgG response beginning in the acute phase of infection. The hypersusceptibility and GC-related phenotypes can be ameliorated by therapy with immune serum procured from Mtb-infected WT mice. We have observed enhanced Mtb susceptibility in two knockout mouse strains defective in GC B cells and follicular helper T cells (Tfh), two major cellular components of GC, supporting a role for GC in defense against Mtb. The S-/- data thus suggest that in the acute phase of infection, IgM plays an important role in the development of an optimal GC reaction that is required, at least in part, for establishing effective adaptive immunity for the control of chronic TB. We recently observed that the levels of lung CD4+ T cells and Th1 cells are increased in the hypersusceptible S-/- mice relative to WT animals during infection. As functionally distinct Th1 subsets (defined by differential expression of PD1 and KLRG1) that can be protective or detrimental to a tuberculous host have recently been described, the seemingly paradoxical S-/- T cell phenotype warrants further characterization, particularly in the context of the newly described Th1 subsets. IgM can mediate antimicrobial activities by modulating opsonization, dendritic cell functions, T cell immunity and humoral responses. Both natural and immune IgMs play a protective role against a variety of pathogens including intracellular bacteria. Of note, we have detected Mtb Ag-specific IgM in the circulation of both naϊve and infected mice and macaques. Mtb-specific IgM is also present in brochoalveolar lavage fluids (BALF) of uninfected and infected monkeys, suggesting that natural and immune IgM may both play a role in regulating anti-TB immunity, possible beginning in the early innate phase of Mtb-host interaction. Based on the above, we posit that: (i) IgM plays a role in optimizing the immune response to Mtb, possibly at the very early phase of infection in the lungs; (ii) IgM is required for establishing an optimal GC reaction that is required for the development of effective adaptive immunity for the control of chronic TB; (iii) natural IgM may play an important role in modulating the host response to Mtb. This proposal will rigorously test these hypotheses using both mouse and monkey TB models. We will use a variety of genetically altered mouse strains which lack specific Ig isotypes, together with bone marrow chimeras, serum therapy, and IgM-coated Mtb to probe the significance of natural and immune IgM in regulating TB immunity. We will also use an ex vivo macaque infection model that enables the evaluation of the effect of IgM on the interaction of Mtb with NHP alveolar macrophages. We believe the combined mouse and monkey approach will shed light on the role of IgM in defense against Mtb, provide mechanistic insights into how this Ab isotype regulates anti-tuberculous responses, and yield information to guide future work on the humoral immunity and natural resistance in TB and the design of novel interventions against the tubercle bacillus, including vaccines.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	000	6	4/29/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	001	6	10/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$429,018
2024	2022	RUTGERS, THE STATE UNIVERSITY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	5	10/11/2023	NON-COMPETING CONTINUATION	-$429,018
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $736,298 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	001	6	1/26/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$736,298
2023	2022	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	5	1/26/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $736,298

Issue Date FY: 2022 ( Subtotal = $747,370 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	005	5	8/4/2022	NON-COMPETING CONTINUATION	$58,000
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	002	5	1/14/2022	NON-COMPETING CONTINUATION	$689,370
2022	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	003	3	5/13/2022	NON-COMPETING CONTINUATION	-$397,035
2022	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	001	4	12/20/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$44,788
2022	2021	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	185 S ORANGE AVE	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	004	4	5/13/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$397,035
2022	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	3	12/20/2021	NON-COMPETING CONTINUATION	-$44,788
														Subtotal = $747,370

Issue Date FY: 2021 ( Subtotal = $730,598 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	3	1/19/2021	NON-COMPETING CONTINUATION	$730,598
														Subtotal = $730,598

Issue Date FY: 2020 ( Subtotal = $727,759 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	2	1/21/2020	NON-COMPETING CONTINUATION	$727,759
														Subtotal = $727,759

Issue Date FY: 2019 ( Subtotal = $700,549 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	2/14/2019	NEW	$700,549
														Subtotal = $700,549

Grand Total All Awards = $3,642,574

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IgM in the regulation of TB immunity

Award Number: R01AI139297

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/15/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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