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Article ; Online: Nicotinamide pathways as the root cause of sepsis - an evolutionary perspective on macrophage energetic shifts.

Suchard, Melinda S / Savulescu, Dana M

2021 Volume 289, Issue 4, Page(s) 955–964

Abstract: Divergent pathways of macrophage metabolism occur during infection, notably switching between oxidative phosphorylation and aerobic glycolysis (Warburg-like metabolism). Concurrently, macrophages shift between alternate and classical activation. A key ... ...

Abstract	Divergent pathways of macrophage metabolism occur during infection, notably switching between oxidative phosphorylation and aerobic glycolysis (Warburg-like metabolism). Concurrently, macrophages shift between alternate and classical activation. A key enzyme upregulated in alternatively activated macrophages is indoleamine 2,3-dioxygenase, which converts tryptophan to kynurenine for de novo synthesis of nicotinamide. Nicotinamide can be used to replenish cellular NAD
MeSH term(s)	Animals ; Biological Evolution ; COVID-19/complications ; Energy Metabolism ; Humans ; Macrophages/immunology ; Macrophages/metabolism ; Niacinamide/metabolism ; Sepsis/etiology ; Sepsis/metabolism
Chemical Substances	Niacinamide (25X51I8RD4)
Language	English
Publishing date	2021-03-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.15807
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Article: Nicotinamide pathways as the root cause of sepsis – an evolutionary perspective on macrophage energetic shifts

Suchard, Melinda S. / Savulescu, Dana M.

FEBS journal. 2022 Feb., v. 289, no. 4

2022

Abstract: Divergent pathways of macrophage metabolism occur during infection, notably switching between oxidative phosphorylation and aerobic glycolysis (Warburg‐like metabolism). Concurrently, macrophages shift between alternate and classical activation. A key ... ...

Abstract	Divergent pathways of macrophage metabolism occur during infection, notably switching between oxidative phosphorylation and aerobic glycolysis (Warburg‐like metabolism). Concurrently, macrophages shift between alternate and classical activation. A key enzyme upregulated in alternatively activated macrophages is indoleamine 2,3‐dioxygenase, which converts tryptophan to kynurenine for de novo synthesis of nicotinamide. Nicotinamide can be used to replenish cellular NAD⁺ supplies. We hypothesize that an insufficient cellular NAD⁺ supply is the root cause of metabolic shifts in macrophages. We assert that manipulation of nicotinamide pathways may correct deleterious immune responses. We propose evaluation of nicotinamide (Vitamin B3) and analogues, including isoniazid, nicotinamide mononucleotide and nicotinamide riboside, as potential therapy for infectious causes of sepsis, including COVID‐19.
Keywords	COVID-19 infection ; glycolysis ; indoleamine 2,3-dioxygenase ; isoniazid ; kynurenine ; macrophages ; niacin ; nicotinamide ; oxidative phosphorylation ; therapeutics ; tryptophan
Language	English
Dates of publication	2022-02
Size	p. 955-964.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	REVIEW
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.15807
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Article ; Online: Immunogenicity of a combined schedule of trivalent oral and inactivated polio vaccines in South African infants.

Moonsamy, Shelina / Suchard, Melinda S / Madhi, Shabir A

Expert review of vaccines

2019 Volume 18, Issue 7, Page(s) 751–754

Abstract: ... ...

Abstract	Background
MeSH term(s)	Antibodies, Neutralizing/immunology ; Cohort Studies ; Humans ; Immunization Schedule ; Immunogenicity, Vaccine ; Infant ; Infant, Newborn ; Poliomyelitis/prevention & control ; Poliovirus Vaccine, Inactivated/administration & dosage ; Poliovirus Vaccine, Inactivated/immunology ; Poliovirus Vaccine, Oral/administration & dosage ; Poliovirus Vaccine, Oral/immunology ; Retrospective Studies ; South Africa
Chemical Substances	Antibodies, Neutralizing ; Poliovirus Vaccine, Inactivated ; Poliovirus Vaccine, Oral
Language	English
Publishing date	2019-06-13
Publishing country	England
Document type	Comparative Study ; Journal Article
ZDB-ID	2181284-6
ISSN	1744-8395 ; 1476-0584
ISSN (online)	1744-8395
ISSN	1476-0584
DOI	10.1080/14760584.2019.1627878
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Article: Stem Cell Transplant in Immune-deficiency-associated Vaccine-derived Poliovirus.

Ranchod, Heena / Howard, Wayne / Roux, Adele / van Zyl, Walda / Ekermans, Pieter / van den Berg, Sylvia / Seakamela, Lerato / Makua, Koketso / Yousif, Mukhlid / Sibiya, Rosinah / Du Plessis, Heleen / Phalane, Emmanuel / McCarthy, Kerrigan / Moonsamy, Shelina / Reynders, David / Hincks, Jeffrey / Suchard, Melinda S / du Plessis, Nicolette M

Open forum infectious diseases

2024 Volume 11, Issue 2, Page(s) ofad678

Abstract: Patients with severe primary immunodeficiency are at risk for complications from live-attenuated vaccines. Here, we report a case of a vaccine-associated paralytic polio and Bacille Calmette-Guérin disease in a 6-month-old girl with severe combined ... ...

Abstract	Patients with severe primary immunodeficiency are at risk for complications from live-attenuated vaccines. Here, we report a case of a vaccine-associated paralytic polio and Bacille Calmette-Guérin disease in a 6-month-old girl with severe combined immunodeficiency resulting from homozygous recombinant activating gene 1 deficiency. The patient was successfully treated with intravenous immunoglobulins and oral pocapavir for poliovirus, and antimycobacterial therapy for regional Bacille Calmette-Guérin disease, allowing stem cell transplant. Following transplantation, poliovirus type 3 with 13 mutations was detected from cerebrospinal fluid but not from stool, indicating ongoing viral evolution in the central nervous system despite pocapavir treatment. Clinical improvement and immune reconstitution allowed the patient to be successfully discharged with no further detection of poliovirus.
Language	English
Publishing date	2024-01-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2757767-3
ISSN	2328-8957
ISSN	2328-8957
DOI	10.1093/ofid/ofad678
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Article ; Online: Prevalence and incidence rates of laboratory-confirmed hepatitis B infection in South Africa, 2015 to 2019.

Moonsamy, Shelina / Suchard, Melinda / Pillay, Pavitra / Prabdial-Sing, Nishi

BMC public health

2022 Volume 22, Issue 1, Page(s) 29

Abstract: Background: Hepatitis B virus (HBV), a global public health threat, is targeted for elimination by 2030. As national HBV prevalence and incidence is lacking for South Africa, our study aimed to provide such data in the public health sector.: Methods: ...

Abstract	Background: Hepatitis B virus (HBV), a global public health threat, is targeted for elimination by 2030. As national HBV prevalence and incidence is lacking for South Africa, our study aimed to provide such data in the public health sector. Methods: We analysed laboratory-confirmed HBV data from 2015 to 2019 to determine annual prevalence and incidence rates of HBV infection per 100,000 population, HBsAg and anti-HBc IgM test positivity rates, and HBsAg and anti-HBc IgM testing rates per 100,000 population. Time trend and statistical analyses were performed on HBsAg and anti-HBc IgM test positivity rates. Results: The national prevalence rate of HBV infection per 100,000 population increased from 56.14 in 2015 to 67.76 in 2019. Over the five years, the prevalence rate was higher in males than females, highest amongst individuals 25 to 49 years old and highest in Gauteng province. The HBsAg test positivity rate dropped from 9.77% in 2015 to 8.09% in 2019. Over the five years, the HBsAg test positivity rate was higher in males than females, amongst individuals 25 to 49 years old and amongst individuals of Limpopo province. Amongst HBsAg positive children under 5 years old, the majority (65.7%) were less than a year old. HBsAg testing rates per 100,000 population were higher in females under 45 years of age and in males 45 years and above. The national incidence rate of acute HBV infection per 100,000 population dropped from 3.17 in 2015 to 1.69 in 2019. Over the five-year period, incidence rates were similar between males and females, highest amongst individuals 20 to 39 years old and highest in Mpumalanga province. Amongst individuals 20 to 24 years old, there was a substantial decline in the incidence and anti-HBc IgM test positivity rates over time. Anti-HBc IgM testing rates per 100,000 population were higher in females under 40 years of age and in males 40 years and above. Conclusion: Critical to hepatitis B elimination is strengthened infant vaccination coverage and interruption of vertical transmission. Transmission of HBV infection in adults may be reduced through heightened awareness of transmission routes and prevention measures.
MeSH term(s)	Adult ; Child ; Child, Preschool ; Female ; Hepatitis B/diagnosis ; Hepatitis B/epidemiology ; Hepatitis B/prevention & control ; Hepatitis B Antibodies ; Hepatitis B Surface Antigens ; Hepatitis B virus ; Humans ; Immunoglobulin M ; Incidence ; Infant ; Male ; Middle Aged ; Prevalence ; South Africa/epidemiology ; Young Adult
Chemical Substances	Hepatitis B Antibodies ; Hepatitis B Surface Antigens ; Immunoglobulin M
Language	English
Publishing date	2022-01-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2041338-5
ISSN	1471-2458 ; 1471-2458
ISSN (online)	1471-2458
ISSN	1471-2458
DOI	10.1186/s12889-021-12391-3
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Article: Evolutionary Views of Tuberculosis: Indoleamine 2,3‐Dioxygenase Catalyzed Nicotinamide Synthesis Reflects Shifts in Macrophage Metabolism: Indoleamine 2,3‐Dioxygenase Reflects Altered Macrophage Metabolism During Tuberculosis Pathogenesis

Suchard, Melinda S / Adu‐Gyamfi, Clement G / Cumming, Bridgette M / Savulescu, Dana M

BioEssays. 2020 May, v. 42, no. 5

2020

Abstract: Indoleamine 2,3‐dioxygenase (IDO) is the rate‐limiting enzyme in conversion of tryptophan to kynurenines, feeding de novo nicotinamide synthesis. IDO orchestrates materno‐foetal tolerance, increasing human reproductive fitness. IDO mediates immune ... ...

Abstract	Indoleamine 2,3‐dioxygenase (IDO) is the rate‐limiting enzyme in conversion of tryptophan to kynurenines, feeding de novo nicotinamide synthesis. IDO orchestrates materno‐foetal tolerance, increasing human reproductive fitness. IDO mediates immune suppression through depletion of tryptophan required by T lymphocytes and other mechanisms. IDO is expressed by alternatively activated macrophages, suspected to play a key role in tuberculosis (TB) pathogenesis. Unlike its human host, Mycobacterium tuberculosis can synthesize tryptophan, suggesting possible benefit to the host from infection with the microbe. Intriguingly, nicotinamide analogues are used to treat TB. In reviewing this field, it is postulated that flux through the nicotinamide synthesis pathway reflects switching between aerobic glycolysis and oxidative phosphorylation in M. tuberculosis‐infected macrophages. The evolutionary cause of such shifts may be ancient mitochondrial behavior related to reproductive fitness. Evolutionary perspectives on the IDO pathway may elucidate why, after centuries of co‐existence with the Tubercle bacillus, humans still remain susceptible to TB disease.
Keywords	Mycobacterium tuberculosis ; glycolysis ; humans ; indoleamine 2,3-dioxygenase ; kynurenine ; macrophages ; mitochondria ; nicotinamide ; oxidative phosphorylation ; pathogenesis ; reproductive fitness ; tryptophan ; tuberculosis
Language	English
Dates of publication	2020-05
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	NAL-AP-2-clean ; JOURNAL ARTICLE
ZDB-ID	50140-2
ISSN	1521-1878 ; 0265-9247
ISSN (online)	1521-1878
ISSN	0265-9247
DOI	10.1002/bies.201900220
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Article ; Online: Evolutionary Views of Tuberculosis: Indoleamine 2,3-Dioxygenase Catalyzed Nicotinamide Synthesis Reflects Shifts in Macrophage Metabolism: Indoleamine 2,3-Dioxygenase Reflects Altered Macrophage Metabolism During Tuberculosis Pathogenesis.

Suchard, Melinda S / Adu-Gyamfi, Clement G / Cumming, Bridgette M / Savulescu, Dana M

BioEssays : news and reviews in molecular, cellular and developmental biology

2020 Volume 42, Issue 5, Page(s) e1900220

Abstract: Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in conversion of tryptophan to kynurenines, feeding de novo nicotinamide synthesis. IDO orchestrates materno-foetal tolerance, increasing human reproductive fitness. IDO mediates immune ... ...

Abstract	Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in conversion of tryptophan to kynurenines, feeding de novo nicotinamide synthesis. IDO orchestrates materno-foetal tolerance, increasing human reproductive fitness. IDO mediates immune suppression through depletion of tryptophan required by T lymphocytes and other mechanisms. IDO is expressed by alternatively activated macrophages, suspected to play a key role in tuberculosis (TB) pathogenesis. Unlike its human host, Mycobacterium tuberculosis can synthesize tryptophan, suggesting possible benefit to the host from infection with the microbe. Intriguingly, nicotinamide analogues are used to treat TB. In reviewing this field, it is postulated that flux through the nicotinamide synthesis pathway reflects switching between aerobic glycolysis and oxidative phosphorylation in M. tuberculosis-infected macrophages. The evolutionary cause of such shifts may be ancient mitochondrial behavior related to reproductive fitness. Evolutionary perspectives on the IDO pathway may elucidate why, after centuries of co-existence with the Tubercle bacillus, humans still remain susceptible to TB disease.
MeSH term(s)	Catalysis ; Humans ; Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics ; Macrophages ; Niacinamide ; Tuberculosis/genetics
Chemical Substances	Indoleamine-Pyrrole 2,3,-Dioxygenase ; Niacinamide (25X51I8RD4)
Language	English
Publishing date	2020-06-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	50140-2
ISSN	1521-1878 ; 0265-9247
ISSN (online)	1521-1878
ISSN	0265-9247
DOI	10.1002/bies.201900220
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Article ; Online: The show is not over - wild-type polio in Malawi is a wake-up call and an opportunity for elimination efforts.

McCarthy, Kerrigan / Howard, Wayne / Yousif, Mukhlid / Moonsamy, Shelina / Suchard, Melinda

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases

2022 Volume 119, Page(s) 32–33

MeSH term(s)	Disease Eradication ; Humans ; Immunization Programs ; Malawi/epidemiology ; Poliomyelitis/epidemiology ; Poliomyelitis/prevention & control
Language	English
Publishing date	2022-03-05
Publishing country	Canada
Document type	Editorial
ZDB-ID	1331197-9
ISSN	1878-3511 ; 1201-9712
ISSN (online)	1878-3511
ISSN	1201-9712
DOI	10.1016/j.ijid.2022.03.004
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Article ; Online: Alloimmunity to Class 2 Human Leucocyte Antigens May Reduce HIV-1 Acquisition - A Nested Case-Control Study in HIV-1 Serodiscordant Couples.

Suchard, Melinda S / Martinson, Neil / Malfeld, Susan / de Assis Rosa, Debbie / Mackelprang, Romel D / Lingappa, Jairam / Hou, Xuanlin / Rees, Helen / Delany-Moretlwe, Sinead / Goldfein, Hadassa / Ranchod, Heena / Coetzee, David / Otwombe, Kennedy / Morris, Lynn / Tiemessen, Caroline T / Savulescu, Dana M

Frontiers in immunology

2022 Volume 13, Page(s) 813412

Abstract: Enveloped viruses, including the Human Immunodeficiency Virus-1 (HIV), incorporate host proteins such as human leucocyte antigens (HLA) into their envelope. Pre-existing antibodies against HLA, termed HLA antibodies, may bind to these surface proteins ... ...

Abstract	Enveloped viruses, including the Human Immunodeficiency Virus-1 (HIV), incorporate host proteins such as human leucocyte antigens (HLA) into their envelope. Pre-existing antibodies against HLA, termed HLA antibodies, may bind to these surface proteins and reduce viral infectivity. Related evidence includes macaque studies which suggest that xenoimmunization with HLA antigens may protect against simian immunodeficiency virus infection. Since HIV gp120 shows homology with class 2 HLA, including shared affinity for binding to CD4, class 2 HLA antibodies may influence HIV acquisition
MeSH term(s)	Autoantibodies ; Case-Control Studies ; HIV Infections ; HIV-1 ; HLA Antigens ; Humans
Chemical Substances	Autoantibodies ; HLA Antigens
Language	English
Publishing date	2022-03-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.813412
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Article ; Online: Effect of HIV-exposure and timing of anti-retroviral treatment on immunogenicity of trivalent live-attenuated polio vaccine in infants.

Moonsamy, Shelina / Suchard, Melinda / Madhi, Shabir A

PloS one

2019 Volume 14, Issue 4, Page(s) e0215079

Abstract: Introduction: The prevalence of HIV infection in South African pregnant women has been approximately 30% over the past decade; however, there has been a steady decline in mother-to-child transmission of HIV from 8% in 2008 to <2% in 2015. We evaluated ... ...

Abstract	Introduction: The prevalence of HIV infection in South African pregnant women has been approximately 30% over the past decade; however, there has been a steady decline in mother-to-child transmission of HIV from 8% in 2008 to <2% in 2015. We evaluated the immunogenicity of live-attenuated trivalent oral polio vaccine (OPV) following the primary vaccination series (doses at birth, 6, 10 and 14 weeks of age) in HIV-exposed uninfected (HEU), HIV-infected infants initiated on early anti-retroviral treatment (HIV+/ART+), HIV-infected infants on deferred ART (HIV+/ART-) and HIV-unexposed infants (HU) as the referent group. Methods: Serum polio neutralization antibody titres were evaluated to serotype-1, serotype-2 and serotype-3 at 6, 10 and 18 weeks of age. Antibody titres ≥8 were considered seropositive and sero-protective. Results: At 18 weeks of age, following the complete primary series of four OPV doses, no differences in GMTs, percentage of infants with sero-protective titres and median fold change in antibody titre (18 weeks vs 6 weeks) were observed in HEU infants (n = 114) and HIV+/ART+ infants (n = 162) compared to HU infants (n = 104) for the three polio serotypes. However, comparing HIV+/ART- infants (n = 70) to HU infants at 18 weeks of age, we observed significantly lower GMTs for serotype-1 (p = 0.022), serotype-2 (p<0.001) and serotype-3 (p<0.001), significantly lower percentages of infants with sero-protective titres for the three serotypes (p<0.001), and significantly lower median fold change in antibody titre for serotype-1 (p = 0.048), serotype-2 (p = 0.003) and serotype-3 (p = 0.008). Conclusion: Delaying initiation of ART in HIV-infected infants was associated with an attenuated immune response to OPV following a four-dose primary series of vaccines, whereas immune responses to OPV in HIV-infected children initiated on ART early in infancy and HEU children were similar to HU infants.
MeSH term(s)	Anti-Retroviral Agents/therapeutic use ; Antibodies, Viral/immunology ; Female ; HIV/drug effects ; HIV/immunology ; HIV Infections/drug therapy ; HIV Infections/immunology ; HIV Infections/transmission ; HIV Infections/virology ; Humans ; Incidence ; Infant ; Infant, Newborn ; Infectious Disease Transmission, Vertical/statistics & numerical data ; Male ; Poliomyelitis/epidemiology ; Poliomyelitis/immunology ; Poliomyelitis/prevention & control ; Poliovirus/drug effects ; Poliovirus/immunology ; Poliovirus Vaccines/administration & dosage ; Pregnancy ; South Africa/epidemiology ; Vaccination
Chemical Substances	Anti-Retroviral Agents ; Antibodies, Viral ; Poliovirus Vaccines
Language	English
Publishing date	2019-04-19
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0215079
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