After the Floodwaters Recede: The Hidden Infectious Disease Risks Lurking in Standing Water

Cholera

Cholera is caused by oral ingestion of Vibrio cholerae from contaminated water or food, and is one of the most typical "waterborne diseases" following flood disasters. It can cause profuse watery diarrhea and dehydration, with a relatively high case fatality rate among severe patients who do not receive timely treatment. After entering the small intestine, V. cholerae attaches to and colonizes the intestinal wall, releasing its core virulence factor — cholera toxin. This toxin binds to specific receptors on the surface of intestinal epithelial cells, enters the cells, and disrupts normal cell signaling, causing intestinal cells to secrete massive amounts of water and electrolytes — the direct cause of cholera's characteristic profuse watery diarrhea.

Figure 2. Classification and evolution of Vibrio cholerae
(Source: DOI: 10.3389/fmed.2023.1155751)

Recent studies have further elucidated the structural basis of the interaction between cholera toxin (CT) and host receptors. For example, researchers have solved a high-resolution crystal structure of the secondary binding site where the CT B subunit engages fucosylated receptors (such as the Lewis x antigen), providing a molecular basis for understanding differences in cholera susceptibility across blood groups. Other research has explored a "virulence-targeting" strategy, using dietary minerals such as zinc, selenium, and manganese to interfere with V. cholerae motility, adhesion, and toxin secretion — opening new avenues for treatment.

Figure 3. Schematic diagram of cholera toxin and its glycan receptor
(Source: https://doi.org/10.1038/s41598-019-48579-2)

Leptospirosis

Leptospirosis is the quintessential "water-contact disease" of flood disasters. It is caused by pathogenic Leptospira, transmitted through broken skin or mucous membrane contact with water contaminated by animal urine. Severe cases can involve the liver and kidneys and are accompanied by a bleeding tendency, making this a disease that anyone with prolonged water exposure after a flood needs to watch closely. The surface of Leptospira carries a variety of proteins and lipopolysaccharide components that can be recognized by the human immune system, triggering inflammation and immune responses. Unlike many common bacteria, however, these surface components are not easily and fully recognized or cleared by the immune system, allowing the organism to persist in the body for extended periods — one reason the disease can progress to a chronic, relapsing infection.

Figure 4. From infection to immune targets in severe leptospirosis
(Source: doi:10.1155/2012/317950)

Malaria

Malaria is caused by infection with Plasmodium parasites transmitted by Anopheles mosquitoes. Extensive standing water after flooding significantly extends the mosquito-breeding window, and historical data show that malaria incidence can rebound in some flood-affected regions — making it a mosquito-borne disease of particular concern in tropical and subtropical disaster areas. After Plasmodium infects red blood cells, it produces a specialized surface protein called PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1), which causes infected red blood cells to adhere to blood vessel walls. This adhesion can obstruct the microvasculature and impair local blood flow, a key driver of organ damage in severe malaria (particularly cerebral malaria) and also the primary target of the host's immune response.

Figure 5. Life cycle of Plasmodium, involving Anopheles mosquitoes and the human host
(Source: doi: 10.3389/fimmu.2019.01444)

Over the past decade, the field has accumulated substantial new knowledge on the structure of the PfEMP1 family, var gene regulation, and its organ-specific adhesion specificity, and vaccine development targeting PfEMP1 continues to advance. The latest research from 2025 has further focused on identifying the determinants of anti-PfEMP1 antibodies in acquired protective immunity against cerebral malaria, aiming to clarify which antibody features are truly associated with clinical protection. In addition, vaccines such as RTS,S/AS01 have already been rolled out at scale across multiple African countries, with early data showing a significant reduction in malaria-related hospitalizations and deaths among children under five.

Figure 6. PfEMP1-specific IgG induced by natural infection and subunit vaccination
(Source: doi:10.1016/bs.apar.2024.02.001)

Chikungunya (CHIKV)

Chikungunya fever is caused by the Chikungunya virus (CHIKV), transmitted by Aedes mosquitoes. It is characterized mainly by fever and severe joint pain, with symptoms persisting for months in some patients. Since southern China is already a region with active Aedes mosquito populations, the increased standing water after flooding significantly widens the window for mosquito-borne transmission, making this a vector-borne viral disease that warrants close monitoring for weeks to months after a flood. CHIKV relies on a surface protein (E2) to recognize and bind to human cells and initiate invasion, and this protein is also the primary target of host antibody responses aimed at clearing the virus. At the same time, the process of viral entry activates inflammatory responses in immune cells, which is thought to be linked to the persistent joint pain seen after infection.

Figure 7. Schematic of CHIKV protein expression and the structure of the envelope glycoproteins E2/E1
(Source: doi:10.3390/v11111078)

Research on neutralizing antibodies against the E2 protein has been a major focus in the CHIKV field in recent years. Studies have identified a linear epitope at the N-terminus of E2 (E2EP3, amino acids 1–12) as the primary target of early neutralizing IgG responses after infection, and recombinant antigens designed based on this epitope have been shown to induce partial protective immunity. Other groups have developed highly potent neutralizing IgM monoclonal antibodies targeting the E2 N218 epitope, which have demonstrated therapeutic potential in animal models. In addition, small-molecule inhibitors targeting the TLR4 pathway (such as TAK-242) have been shown to significantly reduce inflammatory responses and mortality in CHIKV-infected animal models, offering a new direction for antiviral strategies.

Figure 8. Schematic of the CHIKV E2–E1–Mxra8 interaction
(Source: doi:10.3390/v11111078)

Clostridioides difficile Infection (CDI)

Clostridioides difficile infection is the leading cause of hospital-acquired, antibiotic-associated diarrhea. In settings of densely populated shelters, limited sanitation, and increased antibiotic use after a disaster, the risk rises considerably, with clinical presentations ranging from mild diarrhea to severe pseudomembranous colitis and toxic megacolon. The core of C. difficile pathogenesis lies in the two toxins it secretes — Toxin A and Toxin B. These toxins enter colonic epithelial cells and disrupt normal cell structure and intercellular junctions, ultimately damaging the intestinal barrier, triggering inflammation, and causing cell death — the direct cause of the diarrhea and colitis symptoms.

Figure 9. Mechanism of action of TcdA and TcdB
(Source: https://doi.org/10.3390/microorganisms12051004)

A 2024 cryo-EM study resolved the three-dimensional structure of the TcdB complex with its host receptors from the Frizzled family (FZD1/2/7), revealing the key structural rearrangements required for TcdB receptor recognition. The study also clarified how bezlotoxumab, currently the only approved anti-toxin monoclonal antibody, blocks the TcdB–FZD7 interaction by stabilizing TcdB in its non-binding conformation. In addition, chemical genetic screening has identified small molecules — such as glycyrrhetinic acid — that target virulence-associated metabolic pathways, including adenine deaminase and ATP synthase, to suppress toxin production, offering a new intervention point for "anti-virulence" strategies.

Figure 10. NanoBiT-BRET binding assays define FZD1, 2, and 7 as high-affinity TcdB receptors in the human gastrointestinal tract
(Source: DOI: 10.1016/j.celrep.2024.113727)