Reproductive and Urinary Tract Infections (STIs) PDF

11/19/24 Reproductive and Urinary Tract Infections (and Sexually Transmitted Infections – STIs) Mucosal membranes play a key role in both Both different from Alimentary canal (digestive tract) Sterile at one end (badly) contaminated at...

11/19/24 Reproductive and Urinary Tract Infections (and Sexually Transmitted Infections – STIs) Mucosal membranes play a key role in both Both different from Alimentary canal (digestive tract) Sterile at one end (badly) contaminated at other 3 Urinary Tract Kidneys remove waste and excess fluid – need to dispose (release to outside) Waste fluid down ureters to bladder Released periodically through urethra Protective mechanisms include Sphincter muscles near urethra keep system closed Downward urine flow washes away microorganisms (urine normally cultures as sterile!) Urine contains organic acids, antimicrobial substances Women have shorter urethras, more likely to get UTIs 4 2  11/19/24 UTI Infective Agents Able to attach to urethra walls – resist downward flow of urine Also able to withstand acid, evade macrophages Most common agents are the ones that live near the exit – E. coli, lactobacillus, etc. variants mutated to have the features above. Contributes to a gender difference in UTIs Males – longer urethra (more distance to cover to reach bladder), further from alimentary canal end (anus). Females – shorter urethra, in close proximity to both alimentary canal and vaginal opening – both with a wide range of potential agents. 5 Which infective agent below causes urinary symptoms but DOES NOT infect through the urethra? A Eschericia coli B Schistosoma hematobium C Enterococcus faecolis D Pseudomonas aeruginosa 6 3  11/19/24 Exceptions to the rule Schistosoma hematobium --helminth Infect through skin (immersed in contaminated water) Migrate through body, mate in veins around bladder Eggs penetrate vein walls and tissue. “some” make it into bladder and out to environment 7 More normal Bacterial cystitis: Uropathogenic E. coli (UPEC) have pili that attach to receptors on bladder epithelial cells Death, sloughing of epithelium results, allowing bacteria to enter underlying epithelium via endocytosis Create intracellular bacterial communities (IBCs) Bacteria detach, move into bladder lumen, create IBCs Bacteria establishes chronic reservoir in epithelium that resists antibiotics, is undetected by immune system Filamentous forms observed, help avoid innate immune response 8 4  11/19/24 Genital System - Female two ovaries; two fallopian tubes; uterus; vagina; external genitalia (vulva) includes labia, clitoris Egg (ovum) released each month during ovulation Swept into adjacent fallopian tube If fertilization occurs, ovum moved via cilia to uterus Implants in epithelial lining Otherwise, menstruation Lower end of uterus is cervix Filled with antimicrobial mucus except during menstruation Cervix opens to vagina 9 Genital System - Male Males: testes; various tubes, ducts, glands; penis Testes outside abdominal cavity in scrotum Sperm cells collected in epididymis Carried to urethra by vas deferens Sperm, secretions of prostate gland and seminal vesicles make up semen Antimicrobial properties Systems join at prostate gland Urinary, sexually transmitted pathogens can infect In older men, prostate often enlarges, slows urine flow 10 5  11/19/24 Differentiate: Genital system diseases and Sexually Transmitted Infections (STI/STD) Gential Ssytem Diseases Can be UTI related Also disruptions in microbial ecology, especially of vagina Changes in pH Loss of Normal flora Other, less well understood (e.g., stress?) Example: Vulvo-Vaginal Candidiasis Overgrowth of microbial flora with Candida (yeast) Local inflammation (itching, pain), odor Not transmitted between persons 11 Toxic Shock Syndrome Discussed earlier – High level of growth of a particular strain of Staphylococcus in a protected area (e.g., tampon) – secreting toxin. 12 6  11/19/24 Sexually Transmitted Infections/Diseases (STIs/STDs) Generally, POORLY INFECTIVE agents. Cannot survive long outside of body REQUIRE long term survival in host, evading immune system REQUIRE contact of mucosal membranes between people Enter through mucous membranes of vagina, urethra, rectum, or mouth and throat Can spread to pelvic area of female Can spread to systemic infections in both sexes. Frequently infective while Asymptomatic Do not know transmitting disease to others. Bacterial (and protozoal ) symptoms are usually due to Inflammation! Viral symptoms usually both inflammation and cell destruction Can cause permanent damage, including infertility. 13 Which STI virulence factor most contributes to spread of the disease? A The mechanism of transmission (STI) B Asymptomatic stages C Embarrassment D Fear of Discovery 14 7  11/19/24 Biggest STI “Virulence” factors Embarrassment Fear of discovery Disbelief 15 Epidemiology We know what causes these diseases… Transmitted through body fluids; all sexual contact has risk May be transmitted in absence of symptoms Open sores, inflammation increase risk of HIV infection Fetuses, newborns at risk by transmission from mother Risk increases with more unprotected sex We can detect even asymptomatic cases We know how to stop transmission 16 8  11/19/24 Bacterial STI -- Syphilis Causative Agent: Treponema pallidum Very slender, highly motile spirochete; outer membrane lacks LPS Viewed with dark-field microscopy, silver stain Endoflagella propel in corkscrew-like motion, allow penetration of variety of tissues and organs In nature, only infects humans 17 Syphilis: virulence factors Secrete enzymes that loosen mucous Corkscrew motility helps in penetration of mucous Outer membrane proteins Outer-membrane proteins bind to host cells Coat themselves with host proteins (fibronectin) – inhibits phagocytosis! 18 9  11/19/24 Progress of disease – infective dose ca 100 bacteria. Penetrates near area of contact Multiplies in localized area of genitalia Localized inflammatory response causes a hard “Chancre” Visible on external genitalia (e.g., penis) Not so much on internal membranes (e.g., vagina or anus) Resolves in 2 to six weeks, much to patient’s relief… à Primary Syphilis 19 What you don’t see… Infection has already spread to lymph nodes and bloodstream. Bacteria distribute system wide, but work to evade bulk of immune response. Microscopic analysis of tissue reveals bacteria and inflammatory cells. Can detect circulating bacteria at a low level. Not as infectious 20 10  11/19/24 Secondary Syphilis Asymptomatic stages actually a war between inflammatory response and bacteria growth – with neither side winning. If syphilis gets upper hand – body can display many infectious lesions on both skin and mucous membranes. Can happen due to immune system stress Can never happen in a lifetime No longer an STI/SD -- > every lesion a potential source of infection. Just needs to touch a mucous membrane. 21 Tertiary Syphilis Major systemic disease. Usually only after years of untreated primary and latent disease, but can happen at any stage Gummatous syphilis – chronic granulomas (see picture) Cardiovascular syphilis – infections of ascending aorta, causing aneurysms. Neurosyphilis – has crossed the blood- brain barrier causing inflammation in brain. Full range of neuro symptoms possible. 22 11  11/19/24 Note done yet: Congenital Syphilis Systemic T. pallidum can easily cross placenta in pregnant women Can occur in absence of any signs or symptoms in mother, and at any stage of pregnancy Damage to fetus usually not until fourth month Spontaneous abortion, stillbirth, and neonatal death common; nearly all survivors develop signs, symptoms Early signs resemble adult secondary syphilis Late symptoms occur after 2 years; bones, cartilage, teeth can become deformed; eye inflammation, deafness General Practice to test all pregnant women for syphilis early in fetal development 23 Where did Syphilis start? Only four human treponeme diseases known – Yaws, Pinta, and Bejel Transmitted by contact or shared cooking/eating utensils. Often associated with poverty or poor sanitation Most limited to tropical environment. One idea is that movement of infected people (and infections) to colder climate spurred development of what we know as syphilis. 24 12  11/19/24 Embarrassment, Fear, and Denial Tracking origin and spread complicated by these factors. Wherever it occurs – it is clearly NOT caused by our wholesome, God fearing lads and lasses, but by the loathsome, debauched persons of that country over there. Or that group over here. Is clear that European seamen (think Columbus) brought back from either Africa or the Americas (and potentially spread from one to the other), and their return to Europe could match the timing of the appearance of disease. Tracking and attempts to stop spread across Europe limited by above. Populations exiled. Armies and seamen blamed. Even names: French pox, English pox, Spanish pox, Neapolitan pox, etc. For a full treatment, see:. https://pmc.ncbi.nlm.nih.gov/articles/PMC3956094/ 25 Whatever the biases -- Spread worldwide Now number three STI in US, even though (mostly) curable with penicillin derivatives Not enough to cure the patient. àNeed to trace back to all past partners àAnd then trace forward to all partners (and back…_ Would you be honest in such a survey? Would your friends? 26 13  11/19/24 Viral STI – Human Immunodeficiency Virus Since we are talking about non-rational resposnes based on embarrassment, fear, and denial, let’s start there…. In 1981, a small group of young men were found to have life threatening infections of mold. They happened to be homosexuals And we are back to years (decades?) of struggle against embarrassment, fear, and denial. All efforts to identify cause and to block spread focused on gay men. In Hindsight – was already a global infection (found in every major city in the world) Unique feature of the original group was that they had good health insurance... 27 You can guess the story from here... Pick on Africa (because, hind sight again, this was the source) Every country with hospitals had at least a full wing of patients dying with the disease. But, first would deny they were there (wards off limits) If admitted they were there, they were filled with refugees from If local researchers (e.g., malaria and trypanosome researchers) found out about wards, they were threatened with expulsion if they spread any lies about our wholesome, God fearing men and women. U.S. wasn’t doing much better. But focus was on groups instead of nationalities. 28 14  11/19/24 What we now know... Causative agent is (one of ) the Human Immunodeficiency Virus(es) HIV-1 is a enveloped, single stranded RNA+ virus, les than 10,000 bases Two copies of the genome inside capsid. Carries three critical enzymes within the capsid/virion Reverse Transcriptase (ET) Integrase HIV Protease 29 30 15  11/19/24 Virus attaches to CD4 surface protein -- Found on Helper T cells, macrophages, and dendritic cells. (then needs to bind to a second co-receptor Membranes fuse – capsid enters cytoplasm. Moves to nucleus RT enzyme converts ssRNA+ to dsDNA. Released inside nucleus. Integrase inserts viral genome into host genome! Tons of mistakes in sequence Viral genome used for Transcription and Translation More mistakes! Virus assembles in cytoplasm and buds from host cell, gaining envelope. 31 Pathology Mutation rate very high Full systemic infection generates every possible mutation in 10Kb genome every 24 hours Some not viable But others change surface antigens and develop drug resistance rapidly! Macrophages and Dendritic cells survive, but act as a reservoir for infection. Can be latent, incorporated into genome è drugs won’t kill Chance for CRISPR to go after integrated genome, but still experimental Bigger problem is that it kills CD4 Lymphocytes – Helper T Cells Body works to produce more, but untreated, CD4 cell number will slowly decline. Normal – 500 – 1200 cells/mm3 If drops to 200 or below, serious immune deficiency – AIDS disease 32 16  11/19/24 Disease Progression 33 Pathology Below 2000 cells /mm3 – opportunistic infections become life threatening AIDS Defining conditions Kaposi sarcoma Pneumocystis pneumonia Toxoplasma Chronic Cryptosporidia Etc. 34 17  11/19/24 So what happened in 1970’s (& before?) HIV found in many bodily fluids of infected person (or animal), but not especially infective. Speculate that hunters in Africa were infected through blood contact with chimpanzee carrying a similar virus. Tracing back through stored blood and serum samples – estimate initial exposure was Spread unnoticed through human populations. One estimate is fewer than 100 cases before mid 1950’s. In 1950’s several factors likely contributed More frequent use of injectables in medical treatment (reusing syringes!) Refugee crisis, overpopulated cities and high unemployment – increased participation in sex work. Development of a new mutation in virus that spread more rapidly. International technical assistance brought advisors to Congo (e.g., Haitian workers) – took back to Haiti. International sex tourism had begun transmitting worldwide in 70’s. Identified (retrospectively) in 79’s in San Francisco and New York. AIDS takes time to manifest Norway family died of AIDS (retrospectively) in 1976 – suspected transmittal in 1960s.. African infections now recognized as AIDS related recorded in 70’s 35 Why didn’t we notice it in Africa? Tuberculosis... When CD4 cells drop below 200, lots of strange diseases crop up. But, before that, when CD4 cells drop below about 400, latent tuberculosis reactivates. In the late 70’s, we didn’t see an AIDS epidemic in Africa – we saw a tuberculosis epidemic, with increasing drug resistant strains. 36 18  11/19/24 Drug treatments The death of AIDS patients was generally due to the other infections, not HIV. For a time – tried to develop new medications that could actually cure Cryptosporidia or Toxo. Answer came with triple therapy (ART) for HIV CD4 cells recover to a degree Opportunistic infections come more under control Currently, can control New drugs (talked about last week) But side effects and cost are high. Does not eliminate provirus, incorporated into genome. 37 Infection Virus cannot move in mucous – requires contact with cell membrane Facilitated by damage to membrane (micro-tears) Anal epithelium not as robust as vaginal. Anal sex better at transmission than vaginal sex Also transmitted by shared needles or blood exchange. It is NOT SPREAD by insect bites or casual contact with sweat, urine, saliva, or tears. 38 19  11/19/24 Vertical Transmission Under U.S. Standard of Care conditions (drug treatment keeping viral loads low), HIV infected mothers will NOT transmit through the placenta, in utero. Can still infect the baby during passage through the birth canal – But this can be remedied by C-section instead of vaginal birth. 39 STIs/STDs -- summary Personal Fight against Embarrassment, Fear, and Disbelief Abstinence, Monogamy or just honest conversations help Testing and Condoms. Possible vaccine or prophylaxis Societal Fight against Embarrassment, Fear, and Disbelief Get testing and medical care to where it is needed, not just to those that can afford it. à You are protecting yourself and your family 40 20