THE ROLE OF INFECTIONS IN THE EMERGENCE OF NON –

COMMUNICABLE DISEASES (NCDs): Compelling needs for novel strategies.

By PROF. G. C. ONYEMELUKWE (MON)

FORMER CHAIRMAN FEDERAL MINISTRY OF HEALTH EXPERT COMMITTEE ON NCDs

NON COMMUNICABLE DISEASES AND RISK FACTORS

INTRAUTERINE INFECTIONS AND FOETAL IMPRINTING BAKER’S HYPOTHESIS

I. Foetal malnutrition and stress(infection)II. Foetal programming, Immune programmingIII. Intrauterine growth retardation(low birth weight)

A. INSULIN RESISTANCE, NIDDM, HYPERTENSION, STROKE, CORONARY HEART DISEASE IN ADULT LIFE. UTI, TOXOPLASMA, RUBELLA, CMV, HERPES. FORRESTAL T. HISTORIC EARLY LIFE ORIGINS OF HYPERTENSION IN AFRICA. J. Nutr.2004:134:211-6.

B. PSYCHOLOGICAL; SCHIZOPHRENIA - CYTOKINE INDUCED PROBLEM DURING FOETAL NEURODEVELOPMENT BY RUBELLA, INFLUENZA, TOXOPLASMOSIS

BROWN. A. PRENATAL INFECTIONS AS RISK FOR SCHIZOPHRENIA. SCHIZOPHRENIA BULL 2006;32(2); 200-202.DOGRA S. V. INTRAUTERINE GROWTH.

C. MALARIA SCHISTOMIASIS IN MOTHER MAKES TH2 RESPONSE ˃ TH1 RESPONSE IN CHILDHOOD.

CLASSIFICATIONS OF INFECTIONSINTRACELLULAR AND EXTRACELLULAR1.BACTERIA2.VIRUSES3.CHLAMYDIA4.PARASITES5.PRIONS

Cell mediated

INNATE SYSTEM WORKS WITH ADAPTIVE IMMUNE SYSTEM

MECHANISMSTOXINSENDOTOXIN

MIMICRYRheumatic fever/

Rheumatic diseaseINDUCE AUTOIMMUNE TYPE I - IV

PRION/CALCIFICATION

HOST/IMMUNE – PARASITE/INFECTION INTERACTION

AGGRESSINS

IMMUNOSUPPRESSION

ONCOGENE±CO-CARCINOGEN

SUPPRESSION OF AUTOIMMUNITY (Plasmodium

knowelsi on NZB mice)CELLULAR DIFFERENTIATION (Ad – 36 virus – Adipocyte)

PERSISTENCE/ TRANSFORMATION CHRONIC INFLAMMATION

MODULATION OFTH1/TH2/T(REG)BALANCE

CYTOKINECHEMOKINES

GENE PRESSURE (MALARIA)1. Sickle gene2. Thalasemia3. G6PD

HYPERSENSITIVITY(TYPE I – V)

STRESS

INFECTIONS

CRIME/VIOLENCECHRONIC

STRESS

ANXIETY DEPRESSION

PSYCHONEUROIMMUNOLOGY

NEUROENDOCRINEIMMUNE AXISSTRESS INDUCED MEMORY DYSFUNCTION

IL-6HEART DISEASE ARTHRITIS

INFECTIONS AND STRESS

OBESITY OF INFECTIOUS ORIGIN

Nikhil V. Dhurandhar, PhD; Richard L. Atkinson,MD; Aftab Ahmed,PhD. GGH JOURNAL.COM 2004:20(3)

A

FAT CELL IN ENERGY HOMEOSTASIS, INFLAMATION, IMMUNITY

1. RESISTIN2. LEPTIN3. ADIPONECTIN INSULIN RESISTANCE4. VISFATIN5. APELIN6. TUMOUR NECROSIS FACTOR (TNF)7. RETINOL BINDING PROTEIN8. MONOCYTE CHEMOTACTIC PROTEIN1 (MCP-1)9. PLASMINOGEN ACTIVATOR INHIBITOR 1 (PAI-1)10. INTERLEUKIN 6

ABDOMINAL FAT CELL IS ACTIVE

PATHOGENS RESPONSIBLE FOR OBESITYPATHOGEN

(REFERENCE)ANIMAL MODEL POSSIBLE

MECHANISM(S)*Human adenovirus(11,15,16)

Chickens, mice, nonhumanprimates

Up-regulation of preadipocytedifferentiation

Human adenovirus(33) Chickens Unknown

SMAM-1 adenovirus (8,9) Chickens Unknown

Borna-disease virus (10,50,51) Rats Hypothalamic damage

Chlamydia pneumoniae(68) No animal model,associated with weightgain in humans

Unknown

Scrapie agent (76-79) Mice Hypothalamic-pituitaryadrenalaxis damage

Canine Distemper virus (5) Mice Hypothalamic damage,reduced hypothalamicleptin receptor expression

Rous-Associated virus-7 (6,7) Chickens Reduced thyroid hormonelevels

* Human pathogens, and/or associated with human obesity.

AdenovirusAd-36:Up-regulationof fat celldifferentiation,reduced leptinsecretion.

Borna-disease virus(BDV)Hypothalamic damage

Hypothalamus

Scrapie agentHypothalamic-pituitaryadrenalaxis damageGLUT-1 Alterations

Rous virus-7RAV-7: Reduced thyroidhormone levels

Adipose tissue

ChlamydiapneumoniaImmunomodulators(?)

ADIPOGENIC PATHOGENS AND THE POTENTIAL MECHANISMS LEADING TO OBESITY

Canine distempervirus (CDV)1. Reduced catecholamineLevels2. Hypothalamicdamage3. Reduced expressionof hypothalamicleptin receptor4. Down-regulation ofMelanin- concentratinghormoneprecursor mRNA

METABOLIC SYNDROME AND ALTERED GUT MICROBIOTA IN MICE LACKING TOLL-LIKE RECEPTORS Matam Vijay-Kumar, Jesse D. Aitken, Frederic A. Carvalho, Tyler C. Cullender, Simon Mwangi, Shanthi Srinivasan, Shanthi V. Sitaraman, Rob Knight, Ruth E. Ley, Andrew T. Gewirtz. Sci 2010, Apr;328 (9): 5975,228-231 DOI: 10.1126/sci.1179721

TLR-5 DEFICIENT MICE cannot recognize PAMP(pathogen associated molecular pattern of bacteria

METABOLIC SYNDROME AND ALTERED GUT MICROBIOTA IN MICE LACKING TOLL-LIKE RECEPTOR doi: 10.1126/science.1179721 Science 9 April 2010: vol. 328 no. 5975 228-231

1. Study found that mice without a protein known as Toll-like receptor 5 (TLR5) of innate immunity in their gut had hyperphagia, gain excessive weight and develop full-blown diabetes and fatty liver disease when fed a high-fat diet.

2. Other studies have shown that the composition of the gut flora differs in people who are obese and diabetic, and people who are normal weight with no metabolic irregularities.3. Other studies have shown that changes in the gut flora can increase the rate at which we absorb fatty acids and carbohydrates, and increase the storage of calories as fat.4. Dysregulated gut flora has been linked to diseases ranging from autism and depression to autoimmune conditions like Hashimoto’s, inflammatory bowel disease and type 1 diabetes.

Metabolic adaptation of C57Bl/6J and SWR/J mice to infection with H. polygyrus. A) Body weights of naïve mice compared to those infected with H. polygyrus for 21 days, Mean ± SEM, N=5–8 in each group; B) Average food intake per 24 hours in naïve vs. 21 day H. polygyrus infected mice, Mean ± SEM, N=5–8 mice per group, *p=0.001; C) A comparison of energy expenditure in naïve vs. H. polygyrus infected SWR/J mice over 24 hours measured by indirect calorimetry, arrows indicate dark cycle period, N=4 mice per group; D) Total ambulatory activity in naïve vs. H. polygyrus infected SWR/J mice over 24 hours, arrows indicate dark cycle period, N=4 mice per group.

CANCER AND INFECTIONSTOTAL INFECTION-ATTRIBUTABLE CANCERS WORLDWIDE

Agent Cancer # cases % all Ca.H. Pylori Stomach 592,000 5.5

Lymphoma 11,500HPV Cervix 492,800 5.2

Anogenital 53,880Oropharynx 14,500

HBV, HCV Liver 535,000 4.9EBV Nasopharynx 78,100 1.0

Hodgkin L. 28,600Burkitt L. 6,700

HIV/HHV8 Kaposi sarcoma 66,200 0.9Non-Hod. L. 36,100

Schistosomes Bladder

10,600 0.1

HTLV-1 ATL 3,300 0.03Liver flukes Bile duct 2,500 0.02Total 1,932,800 17.8

B

I-A Ca in Developing and Developed CountriesDeveloped Countries Developing Countries

Site Agent # cases % all Ca # cases % all Ca.Liver HBV,HCV 48,000 1.0 475,000 8.2

Flukes 0 2,500Cervix HPV 83,400 1.7 409,400 7.0Stomach H. pylori 192,000 3.8 400,000 6.9Kaposi HHV8 3,700 0.1 62,500 1.1NHL HIV/EBV 9,300 0.2 26,800 0.7

EBV (BL) 100 6,600H.pylori 5,600 5,900HTLV-1 550 2,790

Anogenital HPV 22,450 0.4 31,430 0.5Nasopharynx

EBV 6,500 0.1 71,600 1.2

Oropharynx HPV 5,600 0.1 8,800 0.2Hodgkin L. EBV 11,500 0.2 17,100 0.3Bladder Schistos 0 0.0 10,600 0.2Total 389,000 7.7 1,527,000 26.3

COULD INFECTIONS CAUSE PROSTRATE CANCER? IS A VIRUS INVOLVED?1. Robert Schlaberg in 2006 found a virus called Xenotropic

murine-like retrovirus, or XMRV, in the cell samples from prostate cancer patients. RNaseL gene, XMRV is one of the retroviruses.

IS A PARASITE INVOLVED?2. Parasites called Trichomonas vaginalis (T. vaginalis) Casey, G et al.(2002),32 (4), 581-583

doi:10.1038/ng1021; Urisman, A et al.(2006) RNASEL Variant PLoS; Pathogens, 2 (3) doi:10.1371 Stark, J. et al.(2009),JNCI .doi:10.1093.

PRINCIPLES OF ONCOLOGY• Uncontrolled proliferation induces apoptosis

Noxa, Puma

p53

Bak,BaxBclxL,Mc1

Noxa, PumaBclxL, Mcl1

Cyt C

caspases

Mule

Bak/Bax

NATURAL HISTORY OF CERVICAL HPV INFECTIONS

Atypia/ASCUS/CIN1-2/LSIL CIN2-3/CIS/HSIL

STRATEGIES FOR HPV VACCINATION

Prevent InfectionMediate Regression

Eliminate Residual Disease

HBV and HCV in the etiology of Hepatocellular Carcinoma

• Prevalence of HCC is correlated with endemic chronic infection with HBV and HCV• Chronic HBV and HCV infections result in cirrhosis in ~ 15% of subjects in 25-30 years, with HCC arising in ~1% of subjects with cirrhosis.• Non-viral cirrhosis is also a risk factor for HCC.

HCC only arises in the context of cirrhosis.

Hepatitis viruses are very diverse

• Hepatitis C virus (HCV) is a positive strand RNA Flavivirus.

HCV core induces signalling pathwaysE2 interferes with interferon signalling

EBV is associated with multiple cancers

• Burkitt’s lymphoma• Post transplant lymphomas• Hodgkin’s lymphoma• Nasopharyngeal carcinoma• Gastric cancer

EBV is associated with multiple cancers

• EBV infection occurs in > 90% of the population; cancer is very rare.• Most EBV associated cancers are associated with immunosuppression - transplantation (drugs); HIV; malaria;• EBV causes cancer in both B cells, where the virus is latent and productive, and in epithelial cells that do not support viral latency.

EBV associated cancers

PTLDEBNAs1-3, LMPs1-2b

Hodgkin’sEBNA1, LMP1,2A

Burkitt’sEBNA1 only

OtherBcells

NaïveBcell

GerminalCenter

MemoryBcell

EBV associated cancers

Epithelialcell

NasopharyngealCarcinomaEBNA1, LMP1, 2a

Plasmacells

Memory B cell

HHV-8 (KSHV) and Cancer

• Kaposi’s sarcoma - spindle cell (endothelial origin)• Pulmonary Effusion Lymphoma• Multicentric Castleman’s Disease - B cell (non- cancer)Viral genome encodes homologues for cellular genes that block innate and adaptive immunity,block apoptosis, induce proliferation.

STAGES IN DEVELOPMENT OF CANCER

1. Protooncogenes (c-onc genes) are the cellular counterparts of v-onc genes. Their functions are cellular growth and development. The activation of c-onc genes with mutation leads to

uncontrolled cell growth.a. Growth factorsb. Growth factor receptorsc. Signal transducersd. Transcription factors

2. Antioncogenes (tumor suppressor genes). When these genes lose their suppressive effects, unpreventable growth occurs. a. Retinoblastoma gene (Rb) b. p53 c. Wilms tumor gene (WTI) d. VHL gene in Von-Hippel Lindau syndrome e. NF1 and NF2 genes in neurofi bromatosis f. APC and DCC genes in familial adenomatous polyposis

HUMAN ONCOGENIC DNA VIRUSESTAXONOMIC GROUPING EXAMPLES TUMOR TYPES

Adenoviridae Adenovirus types 9, 12, 18, 31 Various solid tumors in rodents

Hepadnaviridae HBV Hepatocellular carcinomaHerpesviridae EBV Burkitt’s lymphoma

Nasopharyngeal carcinoma

B-cell lymphomaHodgkin’s lymphoma

KSHV (HHV-8) Kaposi’s sarcomaPrimary eff usion lymphoma

Multicentric Castleman’s disease

Papillomaviridae HPV types 6, 11, 16, 18, 31, 45 Oral, cervical, and anal cancer

Merkel cell polyomavirus Merkel cell carcinomaPolyomaviridae BK virus, JC virus Solid tumors in rodentsPoxviridae MCV Various solid tumors

HBV: Hepatitis B virus, EBV: Epstein-Barr virus, KSHV: Kaposi’s sarcoma-associated herpesvirus, HHV: Human herpes virus, HPV:Human papillomavirus, MCV: Molluscum contagiosum virus

HUMAN ONCOGENIC RNA VIRUSES.

Taxonomic grouping

Examples Tumor types

Retroviridae HTLV type 1 Adult T-cell leukemia

Flaviviridae Hepatitis C virus Hepatocellular carcinoma

HTLV: Human T-cell leukemia virus.

NUTRITION AND INFECTIONSPIRAL OF MALNUTRITION AND INFECTION

INADEQUATE DIETARY INTAKE

APPETITE LOSSNUTRIENT LOSS

MALABSORPTIONALTERED METABOLISM

WEIGHT LOSSGROWTH FATTERINGLOWERED IMMUNITYMUCOSAL DAMAGE

DISEASE:INCIDENCE DURATION

SEVERITY

Onyemelukwe GC, Ogoina D, Ibiam G E, GH Ogbadu. Aflatoxins in body fluids and food of Nigerian children with protein- energy malnutrition. Afri. J. of Food, Agriculture, Nutrition and development, 12: (5 )2012 , ISSN 1684 5374 (KWASHIOKOR,MARASMUS,STUNTING.)

AFLATOXINS FROM FUNGI – ASPERGILLUS FLAVUS

HYPERMETABOLISMIL-1,IL-6,TNF, FEVER

PROTEIN LOOSINGENTEROPATHY

C

UNDERNUTRITION INFECTION

DECREASED IMMUNE FUNCTION-INNATE-ACQUIRED

IMPAIRED ABSORPTION. ALTERED GUT LUMEN . MUCOSAL INJURY

CARDIOVASCULAR - ATHEROSCLEROSISD

ATHEROSCLEROSIS IS ASSOCIATED WITH MULTIPLE PATHOGENIC MECHANISMS IN HIV-INFECTED ANTIRETROVIRAL-NAÏVE OR TREATED

INDIVIDUALS.Piconi, Stefania;Parisotto, Serena; Rizzardini, Guiliano; Passerini, Simone; Meraviglia, Paola; Schiavini, Monica; Niero, Fosca; Biasin, Mara; Bonfanti, Paolo; Ricci, Elena Delfina; Trabattoni, Daria; Clerici, Mario. AIDS 2013,27:381-389.

1. HIV- infected patients have a greater burden of sub-clinical and clinical atherosclerotic disease compared to the general population.

2. A complex pathogenesis drives atherogenesis in HIV infection. Thus, whereas inflammation could be responsible for this process in ART-naïve individuals.

3. ABCA-1, an ATP-binding transporter cassette protein involved in cholesterol efflux, which is inhibited by Nef, is up-regulated in ART-treated individuals.

1. CHRONIC HEPATITIS C VIRUS INFECTION IS ASSOCIATED WITH EARLY ATHEROSCLEROSIS. Mostafa et al Gut June 28, 2010.2. Bacterial persistence in phagocyte cells by Dr. Emil Kozarov in

Columbia University: J. Atherosclerosis Thrombosis Bacillus Enterobacter hormaechei chronic infection.

Periodontal bacteria in carotid artery.3. Autoimmunity to heat shock proteins(HSP 60) from bacteria with

autoantibodies in the lesion. Zhu et al 2001. Am.Coll.Cardiol.Florida 850.

4. Individual pathogens CMV, Hepatitis A, Herpes simplex 1 (HSV1), Herpes simplex 2 (HSV2), C.pneumoniae, Helicobacter pylori.

5. Pathogen burden. Zhu J. et al; Am. J. Cardiol.2000, 85: 140-146 of multiple infections with intracellular organisms in (4 )above asociated with elevated C-reactive proteins.

INFLUENZA AND CARDIOVASCULAR DISEASEMohammad Madjid, MD; Ibrahim Aboshady, MD; Imran Awan, MD; Silvio Litovsky, MD; S.Ward Casscells, MD. Tex Heart Inst J 2004; 31:4-13

We appraise the relationship between influenza and coronary heart disease, on the basis of Bradford Hill’s criteria of causality. We show that our proposed relationship meets the following criteria: strength of association, consistency, temporal sequence, coherence, biologic plausibility,experimental evidence, and analogy.

INFECTIOUS AGENTS IMPLICATED IN ATHEROSCLEROSISChlamydia pneumoniaeCytomegalovirusHerpes simplex viruses 1 and 2 (HSV-1, HSV-2)Helicobacter pyloriMycoplasma pneumoniaePorphyromonas gingivalisEnterovirus speciesSalmonella typhiStreptococcus sanguisCoxsackie B virusAdenovirus speciesMycoplasma gallisepticumMarek’s disease virusMeasles virusEpstein-Barr virusHuman immunodeficiency virusMycoplasma fermentansCoxiella burnettiActinobacillus actinomycetemcomitansBacteroides forsythusHepatitis A virusPrevotella intermediaInfluenza virus

EFFECTS OF INFLUENZA ON THE COAGULATION SYSTEM

Target Effect StudyPlatelet aggregation50-53

Increased In vivo human and animal

Platelet count50,54,55

Diminished In vivo and in vitro human

AT III56 Diminished In vivo humanClotting time57 Increased In vivo humanDIC prevalence58 Increased In vivo humanPT61 Prolonged In vivo humanPTT61 Prolonged In vivo humanFibrinogen62 Decreased In vitro humanFactor V61 Diminished In vivo humanFactor VIII61 Diminished In vivo humanFDPs56,61,63 Markedly Increased In vivo and in vitro

humanFibrin monomers63 Positive In vitro humanSoluble fibrin61 Increased In vivo humanStaphylococcal clumping test61

Abnormal In vivo human

Plasminogen Decreased In vivo humaná1-Antitrypsin Reduced In vivo humaná2-Macroglobulin5 Reduced In vivo humanPlasmin inhibitor complexes

Produced, then consumed

In vivo human

Secondary fibrinolysis56

Initiation In vivo human

Tissue factor64,65 Increased In vivo humanFactor VII64 Activation In vivo humanFactor X64 Activation In vivo humanTFPI66 Exhausts the

inhibitory effectIn vivo human

Monocytes Activate the procoagulant

In vivo human

Endothelial cell damage57A. Release of phosphatidyl serineB. Lysis a. Exposure of the prothrombotic extracellular matrix to the vascular lumen b. Alteration of the procoagulant-anticoagulant balance

HILL’S CRITERIA FOR CAUSALITY

Strength of associationConsistencyTemporal sequenceCoherenceBiologic plausibilityBiologic gradient (dose-response relationship)SpecificityExperimental evidenceAnalogy

RECOMMENDATIONS FOR IMPROVING INFLUENZA CONTROL IN CARDIOVASCULAR PATIENTS

• Motivate doctors and patients by increasing recognition ofthe heart-protective effect of flu shots• Update cardiology practice guidelines to include flu shots• Examine the feasibility of financial incentives to doctors andpatients to improve adherence to existing guidelines• Determine which virus strains trigger cardiovascular events• Strengthen educational efforts to persuade pediatricians,internists, gynecologists, and family practitioners to improvevaccination rate of household contacts of patients with heartdisease• Intensify research on the mechanism of the effect of thevirus on the vascular system• Design new clinical trials to determine high-risk groups thatmay benefit from influenza prevention in terms of cardiovascularprevention

PRION DISEASESE

Kajander E (2006). "Nanobacteria--propagating calcifying nanoparticles". Lett Appl Microbiol 42 (6): 549-52. www.nanobac.org

Nanobacteria cause kidney stones and arterial classifications

F AUTOIMMUNE DISEASES AND ALLERGIES

STRACHAN DV BMJ, 1989 – HYGIENE HYPOTHESIS

HYGIENE HYPOTHESIS

I. Worm Therapy.Worm therapy has been or is being studied in humans as a treatment for several immunological diseases including Crohn's disease, Ulcerative Colitis, Multiple Sclerosis, Eczema or atopic dermatitis and allergies. Autoimmune liver disease has also been demonstrated to be modulated by active helminth infections.

II. The Hygiene Hypothesis & Worm therapy.a. Extra-cellular antigens primarily trigger the TH2 response, as observed with allergies, while intracellular antigens trigger a TH1 response. The Hygiene Hypothesis states that there is a regulatory action between the two types of response.b. The Old Friends Hypothesis modifies the Hygiene Hypothesis, proposing that T regulator cells (T regs) only become mature and completely effective if they are stimulated by repeated exposure to microorganisms and parasites that are relatively benign and which have coexisted with humans throughout our evolutionary history.

III. Which worms are used in therapy?Only Necator Americanus meet all these requirements, although Trichuris Suis Ova only , so it is more expensive at therapeutic doses. The main difference between N. americanus and T. suis is residency time, because T. suis has a lifespan of only 2-3 weeks in humans, while N. americanus has an average life span of 5 years.

DC= DENDRITIC CELLS; APC=ANTIGEN PRESENTING CELLS;

DENDRITIC CELLS PRESENTATION OF ANTIGENS LEAD TO FORMATION OF Treg and TISSUE GROWTH FACTOR (TGF-b)

CHILDREN IN WESTERN COUNTRIES VERSUS CHILDREN IN AFRICAN COUNTRIES

IL-25 elicits a multi-potent progenitor cell population thatpromotes Th2 cytokine responses

Steven A. Saenz1, Mark C. Siracusa1, Jacqueline G. Perrigoue1, Sean P. Spencer1, JosephF. Urban Jr.2, Joel E. Tocker3, Alison L. Budelsky3, Melanie A. Kleinschek4, Robert A.Kastelein4, Taku Kambayashi5, Avinash Bhandoola5, and David Artis.Nature. 2010 April 29; 464(7293): 1362–1366. doi:10.1038/nature08901.

PARASITES AND ALLERGIC DISEASES

VACCINATION with Human Hookworm Vaccine "Necator americanus Aspartic Protease-1 M74“ Generates Neutralizing Antibodies and a Potent Immune Response in BALB/c Mice.Amar R. Jariwala, George Washington University; Xi Chen, George Washington University; Mark S. Pearson, James Cook University; Brian Keegan, Baylor College of Medicine; Jill B. Brelsford, George Washington University; Medical Immunology Commons; 4-22-2013

INFANT GUT MICROBIOTA AND THE HYGIENE HYPOTHESIS OF ALLERGIC DISEASE: IMPACT OF HOUSEHOLD PETS AND SIBLINGS ON MICROBIOTA COMPOSITION AND DIVERSITYMeghan B Azad1, Theodore Konya2, Heather Maughan3, David S Guttman3, Catherine J Field4, Malcolm R Sears5, Allan B Becker67, James A Scott2, Anita L Kozyrskyj17* and CHILD Study Investigators7 . Allergy, Asthma & Clinical Immunology 2013, 9:15 doi:10.1186/1710-1492-9-15

Model for the possible influence of pets and siblings on infant gut microbiota and subsequent development of atopic disease. Household pets (D, dogs; C, cats) and siblings increase infant exposure to environmental microbes, promoting enrichment for distinct combinations of organisms within the gut microbiota; overall richness and diversity are also impacted. Despite favoring different microbiota profiles, the net effect of both pets and siblings is to promote healthy immune system development and protect against atopic disease. Further research is required to characterize the underlying biological mechanisms. Azad et al. Allergy, Asthma & Clinical Immunology 2013 9:15 doi:10.1186/1710-1492-9-15

G. MENTAL DISEASES- DEPRESSION AND VIRAL INFECTIONS

Shalini, Malhotra; Nirmaljit, Kaur; P. Kumar; M.S. Bhatia; Charu, Hans. Delhi psychiatry journal vol. 15 no.1

1. Human immunodeficiency virus2. Hepatitis C virus3. Epstein-Barr Virus4. Herpes simplex virus5. Influenza virus6. Hepatitis B virus7. Hepatitis A virus8. BORNA DISEASE VIRUS9. Human T-cell Lymphotropic virus (HTLV) . markers of inflammation (C-reactive protein, interleukin 1 and 6) were positively correlated with depression.43 . Cytokines seem to trigger a quick onset of what is called ‘sickness behavior’-meaning malaise and fatigue, as well as a delayed onset of depressed . etanercept (a TNFtumor necrosis factor-blocker) reduced depressive symptoms in people with psoriasis.

MECHANISM OF ACTION OF MICROBIAL PATHOGENS IN DEPRESSION A. Chronic infection with any of these viruses can lead to raised interferon-alpha levels (interferon-alpha is secreted by cells of the immune system as it tries to control the virus), and it is now known that interferon-alpha can significantly affect the serotonin system.B Coxsackie virus B, which have a particular affinity for, and disruptive action on, the hypothalamus.C. Raising glutamate and quinolinic acid levels in the brain (high glutamate levels are linked to depression). The excess glutamate/quinolinic acid in this case comes from the activated microglia cells (microglia are specialized macrophages permanently resident in the brain).D. Depression can sometimes be caused by low levels of the adrenal hormone cortisol. Viruses like enterovirus often chronically infect the adrenal glands.E. Chronic fatigue syndrome, the working memory and long-term recall is often severely disrupted.

LIST OF NON COMMUNICABLE DISEASES (NCDs) AND THEIR KNOWN OR PROBABLE INECTIOUS RISK FACTORS

CARDIOVASCULAR

H

RESEARCHES IN CARDIOVASCULAR DISEASES1. RHEUMATIC FEVER/ RHEUMATIC HEART

DISEASE- Grp A, B, C streptococcal pharynigitis and skin infections –Ogunbi et al (lagos) J. Epid. Comm. Health 1978 march 3(1) 68-71

2. Endomyocardial fibrosis(EMF) and loa loa induced eosinophilia. Others trichinella spiralis,ascaris, hookworm, toxoplasmosis Andy JJ et al (Calabar, Ife) Acta tropica 1998; 69 127-140 Urhogide A, Falase A (Ibadan) Afri J Med Med Sci 1987, 16 133

3. PERIPARTUM CARDIAC FAILURE (PPCF) Zaria syndrome- salt lake, Hot bath, volume overload ,pre HT, ? Viral

myocarditis Davidson N, Parry E Q J Med N S 1976, 47 431-461, Adesanya c et al Trop. Geog Med 1989, 41 (3) 190-196, Ford l, Abdullahi et al Q J Med 1998 91 93-103Danbauchi SS Trop Doc 2002,32 24-27

4. OTHERS DUE TO MYOCARDITIS from toxoplasmosis, coxsackie B virus and chlamydia. Falase A (Ibadan) Heart vessels Supp 1985 1, 232-35, Cenac A et al(Niger) Med Trop(Mars) 2000,60,2, 137-40

5. ECLAMPSIA AND INFECTION Ekwempu CC(Zaria) Tropical doctor 1980 174-78

Ekwempu CC Int J Gynae Obstect 1980, 18 4, 300-2

NEUROLOGY/ PSYCHIATRY

1. Tropical spastic paraparesis and HTLV1 Roman GC et al Neurology 1985,35, 11582. Epidemic seasonal ataxia and viral (arbovirus)

encephalitis Adamolekun B et al Met Brain Dis 1997, 12, 2513. Post malaria cerebellar ataxia Osuntokun BO Afr J Med Med Sci 1983, sept 3-4 ,

165-1724. Typhoid and Fregoli syndrome(rare persecutory

delusion) Stanley et al (Jos), Nig J Med 2002,4, no 1,jan-march

33-345. Typhoid and neuropsychiatric manifestation Osuntokun et al Arch 1972 Neurol 27 July 7-13

RESEARCHES IN NEUROLOGICAL IN AFRICA

AUTOIMMUNE/ ENDOCRINE

NOTE: EFFECT OF MALARIA PLASMODIUM BERGHEI IN REDUCED INCIDENCE OF AUTOIMMUNE DISEASES. B. M. GREENWOOD; VOLLER. A. SUPPRESSION OF AUTOIMMUNE DISEASE IN NEW ZEALAND MICE ASSOCIATED WITH INFECTION IN MALARIA II. NZB MICE. CLIN.EXP. 1970; IMMUNOL. 71(6) 805-815

GASTROINTESTINAL DISEASES

1. LIVER CIRRHOSIS , HBV AND SCHISTOSOMIASISFAKUNLE Y, ET AL (ZARIA)

2. HBV, HCV,HDV(DELTA VIRUS)OJO S ET AL EAST AFRI MED J,1995 ,72 ,II,719-21

3. HELICOBACTER PYLORI AND PEPTIC ULCERHOLCOMBE C ET AL (MAIDUGURI) TRANS R SOC TROP MED HYG 1994 88,569

4. MALARIA AND TROPICAL SPLENOMEGALY SYNDROME Fakunle Y, Greenwood B, 1976 Trans R Soc Trop Med Hyg 70 346-51

Fakunle Y, Greenwood B,1977 Clin exp Immunol 28, 153-6

RESEARCHES IN GIT DISEASES

RENAL DISEASES

SOME RESEARCHES ON RENAL DISEASES1. QUARTAN MALARIAL NEPHROPATHY Hendricks RG , Adeniyi A (Ibadan) Kidney Int 1979, 16,642. SCABIES AND NEPHRITIS INCLUDING NEPHROTIC SYNDROME Whittle HC et al Trans R Soc Trop Med Hyg 1973 67, 349-363 Abdulrahman m,b 1984 J Inf Mar 8, 100-9 Aikionbare H et al 1984 Nig J Paed 11,2,59-62 3. VIRAL HEPATITIS AND IMMUNE COMPLEX

GLOMERULONEPHRITIS, LEPROSY, YERSINIA ENTEROCOLITICA(BY RENNER .A) ETC.

RESPIRATORY DISEASES

RESEARCHES IN RESPIRATORY DISEASES

1. Asthma and air borne fungi (Aspergillus fumigatus), house dust mite (dermatophagoides farinae/pterysinnus)Lawande R, Onyemelukwe GC (Zaria) Ann allergy 1984 52(1) 47 Onyemelukwe GC (Zaria) et al Ann Allergy 1986 Feb 56(2), 167-70

2. Asthma and hookworm Salako LA N.Eng J Med 1970,283,264

3. Asthma and strongyloides Nwokolo CU, BMJ,1973, 1, 153

VICIOUS CYCLE HYPOTHESIS IN COPD

CANCERS AND OTHER DISEASES

1. Mutation of tumor suppressor gene in codon 249 by aflatoxin in PLCC.

Ndububa et al Afri J Med Sci 2001 30, 125- 127

2. Schistosomiasis and bladder cancers Bedwani R et al(Egypt) Bri J Cancer 1998, 77,1186-9

3. Aflatoxin B1B2 G1 G2(Aspergillus flavus) and PLCC Ndububa et al Afri J.Med Sci 2001 30, 125- 127 Onyemelukwe et al Toxicol Letters,1982 ,56,2, 167-70

RESEARCHES IN CANCER