Fungal Keratitis Research Articles

Pseudonectria keratitis—emerging pathogenic fungi in the eye

BackgroundInfectious keratitis, a significant contributor to blindness, with fungal keratitis accounting for nearly half of cases, poses a formidable diagnostic and therapeutic challenge due to its delayed clinical presentation, prolonged culture times, and the limited availability of effective antifungal medications. Furthermore, infections caused by rare fungal strains warrant equal attention in the management of this condition.Case presentationA case of fungal keratitis was presented, where corneal scraping material culture yielded pink colonies. Lactophenol cotton blue staining revealed distinctive spore formation consistent with the Fusarium species. Further analysis using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) identified the causative agent as Fusarium proliferatum. However, definitive diagnosis of Pseudonectria foliicola infection was confirmed through ITS sequencing. The patient’s recovery was achieved with a combination therapy of voriconazole eye drops and itraconazole systemic treatment.ConclusionPseudonectria foliicola is a plant pathogenic bacterium that has never been reported in human infections before. Therefore, ophthalmologists should consider Pseudonectria foliicola as a possible cause of fungal keratitis, as early identification and timely treatment can help improve vision in most eyes.

Development of itraconazole ocular delivery system using β-cyclodextrin complexation incorporated into dissolving microneedles for potential improvement treatment of fungal keratitis

Itraconazole (ITZ) is one of the broad-spectrum antifungal agents for treating fungal keratitis. In clinical use, ITZ has problems related to its poor solubility in water, which results in low bioavailability when administered orally. To resolve the issue, we formulated ITZ into the inclusion complex (ITZ-IC) system using β-cyclodextrin (β-CD), which can potentially increase the solubility and bioavailability of ITZ. The molecular docking study has confirmed that the binding energy of ITZ with the β-CD was −5.0 kcal/mol, indicating a stable conformation of the prepared inclusion complex. Moreover, this system demonstrated that the inclusion complex could significantly increase the solubility of ITZ up to 4-fold compared to the pure drug. Furthermore, an ocular drug delivery system was developed through dissolving microneedle (DMN) using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA) as polymeric substances. The evaluation results of DMN inclusion complexes (ITZ-IC-DMN) showed excellent mechanical strength and insertion ability. In addition, ITZ-IC-DMN can dissolve rapidly upon application. The ex vivo permeation study revealed that 75.71% (equivalent to 3.79 ± 0.21 mg) of ITZ was permeated through the porcine cornea after 24 h. Essentially, ITZ-IC-DMN exhibited no signs of irritation in the HET-CAM study, indicating its safety for application. In conclusion, this study has successfully developed an inclusion complex formulation containing ITZ using β-CD in the DMN system. This approach holds promise for enhancing the solubility and bioavailability of ITZ through ocular administration.

Etiopathology, Epidemiology, Diagnosis, and Treatment of Fungal Keratitis.

Fungal keratitis (FK) is a severe ocular condition resulting from corneal infection that is prevalent in tropical countries, particularly in developing regions of Asia and Africa. Factors like corneal lens misuse, inappropriate steroid use, and diagnostic challenges have provoked the epidemic. FK causes significant vision impairment, scarring, and ocular deformities. Accurate pathological diagnosis is crucial for effective therapeutic intervention. Topical antifungal therapy with surface healing medications proves effective in preventing fungal-borne ulcers. Managing FK requires a comprehensive understanding of fungal pathogenesis, guiding formulation strategies and preventive measures to curb global ocular blindness. This review provides in-depth insights into FK, covering etiology, epidemiology, pathogenesis, therapeutic interventions, antifungal resistance, limitations, prevention, and future perspectives on ocular surface disease management.

Clinical profile and outcomes of rejection after deep anterior lamellar keratoplasty in keratoconus.

To report the clinical features and management outcomes of rejection after deep anterior lamellar keratoplasty (DALK). The clinical features, indications, predisposing risk factors, management, and outcome of six eyes of six patients with rejection after DALK were analyzed retrospectively. The median time of rejection from the day of surgery was 12 (range 3-36) months. Median duration of symptoms was 4 (range 2-28) days. The indication for DALK was keratoconus in all eyes. The clinical features at presentation included graft haze, vascularization, and melt at the graft-host junction. The risk factors noted were noncompliance to steroids in all eyes, vernal conjunctivitis (four eyes), and eccentric graft (one eye). The rejection episode reversed with topical steroids in all eyes and intravenous methylprednisolone in one eye. One eye developed secondary fungal keratitis after initial recovery and one eye had a second episode of rejection 3 months later, which resulted in progressive vessels and lipid keratopathy in the visual axis. The median best corrected visual acuity was 20/40 (range 20/30-20/200). Severe stromal rejection can present with graft melt. Repeat episodes of rejection can occur on sudden cessation of topical steroids. Prompt recognition of clinical signs and symptoms with timely management helps in quick reversal of the rejection episode. Reversal of graft rejection results in good visual outcomes.

Current therapy and advancements in the treatment of equine fungal keratitis.

Equine fungal keratitis represents a substantial portion of keratitis cases in horses, with fungal involvement identified in approximately half of all infectious keratitis cases. Despite its prevalence, more comprehensive retrospective analyses are needed to better understand this condition. Outcomes vary, with approximately two-thirds of cases achieving complete healing with retained vision, although enucleation is often necessary. Predominant pathogens include Aspergillus and Fusarium, with yeast reported in a minority of cases. Resistance to common antifungal agents among filamentous fungi poses a significant challenge. Advances in diagnostics, including repeat culture and antifungal susceptibility testing, as well as the incorporation of PCR technology, hold promise for improving detection and guiding treatment decisions. Newer antifungals, combination therapies, and innovative modalities such as photodynamic therapy offer hope for improved outcomes. Continued research efforts are essential to further elucidate the epidemiology, pathogenesis, and optimal management strategies for this condition.

Cold atmospheric plasma inactivates Aspergillus flavus and Fusarium keratoplasticum biofilms and conidia in vitro.

Introduction. Aspergillus flavus and Fusarium keratoplasticum are common causative pathogens of fungal keratitis (FK), a severe corneal disease associated with significant morbidity and vision loss. Escalating incidence of antifungal resistance to available antifungal drugs poses a major challenge to FK treatment. Cold atmospheric plasma (CAP) is a pioneering nonpharmacologic antimicrobial intervention that has demonstrated potential as a broad-spectrum antifungal treatment.Gap statement. Previous research highlights biofilm-associated resistance as a critical barrier to effective FK treatment. Although CAP has shown promise against various fungal infections, its efficacy against biofilm and conidial forms of FK pathogens remains inadequately explored.Aim. This study aims to investigate the antifungal efficacy of CAP against clinical fungal keratitis isolates of A. flavus and F. keratoplasticum in vitro.Methodology. Power parameters (22-27 kVpp, 300-400 Hz and 20-80 mA) of a dielectric barrier discharge CAP device were optimized for inactivation of A. flavus biofilms. Optimal applied voltage and total current were applied to F. keratoplasticum biofilms and conidial suspensions of A. flavus and F. keratoplasticum. The antifungal effect of CAP treatment was investigated by evaluating fungal viability through means of metabolic activity, c.f.u. enumeration (c.f.u. ml-1) and biofilm formation.Results. For both fungal species, CAP exhibited strong time-dependent inactivation, achieving greater than 80 % reduction in metabolic activity and c.f.u. ml-1 within 300 s or less, and complete inhibition after 600 s of treatment.Conclusion. Our findings indicate that CAP is a promising broad-spectrum antifungal intervention. CAP treatment effectively reduces fungal viability in both biofilm and conidial suspension cultures of A. flavus and F. keratoplasticum, suggesting its potential as an alternative treatment strategy for fungal keratitis.

Indications and Outcomes of Emergency Keratoplasty in a Major New Zealand Eye Tertiary Referral Center, 2000 to 2021.

To report the indications and outcomes of emergency keratoplasty over a 21-year period in Greenlane Clinical Centre, the major tertiary eye referral center in Auckland, New Zealand (Aotearoa). A retrospective review of medical records of all emergency keratoplasties performed in Greenlane Clinical Centre from January 2000 to September 2021 was conducted. Demographic, preoperative, intraoperative, and 1-year postoperative data were collected. Emergency keratoplasty was performed in 102 eyes of 97 patients (54 men), comprising 5.6% of transplants performed (N = 1830) in this period. The mean age was 53 years (range = 4-95 years, SD = 20). Patients of Māori ethnicity were overrepresented (31%). Corneal perforation was present in 90% of eyes, and microbial keratitis was the most common indication. Bacteria were the most commonly isolated organisms (38%). The mean preoperative and 12-month postoperative best potential corrected distance visual acuity was 1.6 and 1.2 (logMAR), respectively. All cases of therapeutic keratoplasty achieved initial therapeutic success, with no eyes lost or requiring repeat emergency keratoplasty. Complications included nonhealing epithelial defects (19%), cataract (19%), glaucoma (15%), allograft rejection (13%), and corneal melting (5%). Fifteen cases (15%) had documented graft failure at 12 months. Multivariate analysis revealed that younger age was the only statistically significant factor associated with failure at 12 months. Emergency keratoplasty was the indication for 5.6% of keratoplasties performed. Our results compare favorably with those in the literature, possibly because of early intervention and lower incidence of fungal keratitis. The reported overrepresentation of Māori has important implications for health access and delivery in New Zealand.

Deep learning for multi-type infectious keratitis diagnosis: A nationwide, cross-sectional, multicenter study

The main cause of corneal blindness worldwide is keratitis, especially the infectious form caused by bacteria, fungi, viruses, and Acanthamoeba. The key to effective management of infectious keratitis hinges on prompt and precise diagnosis. Nevertheless, the current gold standard, such as cultures of corneal scrapings, remains time-consuming and frequently yields false-negative results. Here, using 23,055 slit-lamp images collected from 12 clinical centers nationwide, this study constructed a clinically feasible deep learning system, DeepIK, that could emulate the diagnostic process of a human expert to identify and differentiate bacterial, fungal, viral, amebic, and noninfectious keratitis. DeepIK exhibited remarkable performance in internal, external, and prospective datasets (all areas under the receiver operating characteristic curves > 0.96) and outperformed three other state-of-the-art algorithms (DenseNet121, InceptionResNetV2, and Swin-Transformer). Our study indicates that DeepIK possesses the capability to assist ophthalmologists in accurately and swiftly identifying various infectious keratitis types from slit-lamp images, thereby facilitating timely and targeted treatment.

Microbial keratitis in the subtropical region of Korea: a comprehensive 12-year retrospective review at a single referral center

ObjectivesTo investigate the epidemiological characteristics and clinical outcomes of culture-proven bacterial and fungal keratitis at a single tertiary referral centre on Jeju Island, South Korea.DesignA retrospective study design.SettingData from a...

A double-masked, sham-controlled trial of rose bengal photodynamic therapy for the treatment of fungal and acanthameoba keratitis: Rose Bengal Electromagnetic Activation with Green Light for Infection Reduction (REAGIR) Study.

Infectious keratitis secondary to fungus or acanthamoeba often has a poor outcome despite receiving the best available medical therapy. In vitro Rose Bengal Photodynamic therapy (RB-PDT) appears to be effective against fungal and acanthamoeba isolates.22,23 In one published series RB-PDT reduced the need for therapeutic penetrating keratoplasty in severe bacterial, fungal, and acanthameoba keratitis not responsive to medical therapy. This international, randomized, sham and placebo controlled 2-arm clinical trial, randomizes patients with smear positive fungal and acanthameoba and smear negative corneal ulcers in a 1:1 fashion to one of two treatment arms: 1) Topical antimicrobial plus sham RB-PDT or 2) Topical antimicrobial plus RB-PDT. We anticipate that RB-PDT will improve best spectacle corrected visual acuity and also reduce complications such as corneal perforation and the need for therapeutic penetrating keratoplasty. This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Our results will be disseminated via clinicaltrials.gov website, meetings, and journal publications. Our data will also be available upon reasonable request. NCT, NCT05110001, Registered November 5, 2021. https://www.clinicaltrials.gov/study/NCT05110001.

The Role of LC3-Associated Phagocytosis Inhibits the Inflammatory Response in Aspergillus fumigatus Keratitis.

The purpose of this study was to investigate the role and mechanism of microtubule-associated protein light chain-3 (LC3)-associated phagocytosis (LAP) in the immune response to Aspergillus fumigatus (A. fumigatus) keratitis. The formation of single-membrane phagosomes was visualized in the corneas of healthy or A. fumigatus-infected humans and C57BL/6 mice using transmission electron microscopy (TEM). Rubicon siRNA (si-Rubicon) was used to block Rubicon expression. RAW 264.7 cells or mice corneas were infected with A. fumigatus with or without pretreatment of si-Rubicon and scrambled siRNA. RAW 264.7 cells were pretreated with Dectin-1 antibody or Dectin-1 overexpressed plasmid and then stimulated with A. fumigatus. Flow cytometry was used to label macrophages in normal and infected corneas of mice. In mice with A. fumigatus keratitis, the severity of the disease was assessed using clinical scores. We used lentiviral technology to transfer GV348-Ubi-GFP-LC3-II-SV40-Puro Lentivirus into the mouse cornea. The GFP-LC3 fusion protein was visualized in corneal slices using a fluorescence microscope. We detected the mRNA and protein expressions of the inflammatory factors IL-6, IL-1β, and IL-10 using real-time PCR (RT-PCR) and ELISA. We detected the expression of LAP-related proteins Rubicon, ATG-7, Beclin-1, and LC3-II using Western blot or immunofluorescence. Accumulation of single-membrane phagosomes within macrophages was observed in the corneas of patients and mice with A. fumigatus keratitis using TEM. Flow cytometry (FCM) analysis results show that the number of macrophages in the cornea of mice significantly increases after infection with A. fumigatus. LAP-related proteins were significantly elevated in the corneas of mice and RAW 264.7 cells after infection with A. fumigatus. The si-Rubicon treatment elevated the clinical score of mice. In A. fumigatus keratitis mice, the si-Rubicon treated group showed significantly higher expression of IL-6 and IL-1β and lower expression of IL-10 and LC3-II compared to the control group. In RAW 264.7 cells, treatment with the Dectin-1 overexpressed plasmid upregulated the expression of LAP-related proteins, a process that was significantly inhibited by the Dectin-1 antibody. LAP participates in the anti-inflammatory immune process of fungal keratitis (FK) and exerts an anti-inflammatory effect. LAP is regulated through the Dectin-1 signaling pathway in A. fumigatus keratitis.

Infectious Keratitis in Patients Over 65: A Review on Treatment and Preserving Eyesight.

Infectious keratitis (IK) represents a significant global health concern, ranking as the fifth leading cause of blindness worldwide despite being largely preventable and treatable. Elderly populations are particularly susceptible due to age-related changes in immune response and corneal structure. However, research on IK in this demographic remains scarce. Age-related alterations such as increased permeability and reduced endothelial cell density further compound susceptibility to infection and hinder healing mechanisms. Additionally, inflammaging, characterized by chronic inflammation that develops with advanced age, disrupts the ocular immune balance, potentially exacerbating IK and other age-related eye diseases. Understanding these mechanisms is paramount for enhancing IK management, especially in elderly patients. This review comprehensively assesses risk factors, clinical characteristics, and management strategies for bacterial, viral, fungal, and acanthamoeba keratitis in the elderly population, offering crucial insights for effective intervention.

The Role of OCT in Follow-Up of Fungal Keratitis Caused by Beauveria bassiana in Contact Lens Wearer.

A 25-year-old Caucasic female was referred to our clinic after suffering from infectious keratitis in the right eye for a month. The patient was a contact lens user and had no history of ocular trauma. Furthermore, the patient did not report any relevant antecedent. The main complaint was intense photophobia and pain. Infectious keratitis remains one of the main complications of contact lens wear and can become a therapeutic challenge in some patients. Although the most frequent causal agent is bacterial, other causes such as herpes virus, Acanthamoeba or fungi should be considered when antimicrobial therapy does not work as expected clinically. Fungal keratitis normally appears on previously damaged corneas, but it can also develop in contact lens wearers. Beauveria bassiana is an unusual pathogen which has been diagnosed more frequently lately per the clinical reports in the last 30 years, so it can be included in the diagnostic scheme when a fungal keratitis is suspected. In clinical management, AS-OCT may be a functional tool to assess the evolution and monitor the response to microbial agents and surgery. Although more studies are needed, some characteristic features have been described and can help to diagnose a fungal keratitis against other infections. AS-OCT can also play an important role in monitoring the corneal scarring after the keratitis episode, and it may be useful to plan post-infection therapy for visual rehabilitation.

Design of Proteolytic-Resistant Antifungal Peptides by Utilizing Minimum d-Amino Acid Ratios.

Antifungal peptides are an appealing alternative to standard antifungal medicines due to their unique mechanism of action and low-level resistance. However, their susceptibility to protease degradation keeps hindering their future development. Herein, a library was established to design peptides with protease resistance and high antifungal activity. The peptides were incorporated with minimal D-amino acids to further improve the protease stability. The most active peptide, IR3, demonstrated good antifungal activity and low toxicity, and its molecular integrity was maintained after protease hydrolysis for 8 h at 2 mg/mL. Furthermore, IR3 could permeate the fungal cell wall, disrupt the cell membrane, produce reactive oxygen species, and induce apoptosis in fungal cells. In vivo experiments confirmed that IR3 could effectively treat fungal keratitis. Collectively, these findings suggest that IR3 is a promising antifungal agent and may be beneficial in the design and development of protease-resistant antifungal peptides.

The Development of an Innovative Ophthalmic In-situ Gel Containing Posaconazole

The goal of this study was to create and test various in-situ gel formulas for administering posaconazole to the eye to treat fungal keratitis. They used an in-situ gelling method to help posaconazole stay in the eye mucosa longer, which made it easier for the body to use. To make in-situ gel preparations, polymers such as sodium alginate, poloxamer 407, and poloxamer 188 were used in a cold method. Finally, there was 0.2% (w/w) posaconazole in the mixtures. The pH, drug content, viscosity, gelling capacity, and temperature at which the solution turns into a gel were all checked on the recipes. It was between 32 and 34℃ when each blend turned into a gel. There was about the same amount of drugs in all of them. It was also worked out how much of the antifungal and in-vitro drugs these mixtures would release. Everyone in the drug release study showed signs of long-lasting release. To sum up, in-situ gels that contain posaconazole could be a good way to use optical drug delivery to change how fungus diseases act.

Progranulin Protects against Aspergillus fumigatus Keratitis by Attenuating the Inflammatory Response through Enhancing Autophagy.

Fungal keratitis (FK) is a severe corneal condition caused by pathogenic fungi and is associated with the virulence of fungi and an excessive tissue inflammatory response. Progranulin (PGRN), functioning as a multifunctional growth factor, exerts a pivotal influence on the regulation of inflammation and autophagy. The aim of our research was to analyze the role of PGRN in Aspergillus fumigatus (A. fumigatus) keratitis. We found that PGRN expression was increased in the mouse cornea with A. fumigatus keratitis. In our experiments, corneas of mice with FK were treated with 100 ng/mL of PGRN. In vitro, RAW 264.7 cells were treated with 10 ng/mL of PGRN before A. fumigatus stimulation. The findings suggested that PGRN effectively alleviated corneal edema and decreased the expression of pro-inflammatory cytokines in mice. In stimulated RAW 264.7 cells, PGRN treatment suppressed the expression of pro-inflammatory cytokines IL-6 and TNF-α but promoted the expression of the anti-inflammatory cytokines IL-10. PGRN treatment significantly upregulated the expression of autophagy-related proteins LC3, Beclin-1, and Atg-7. 3-Methyladenine (3-MA, autophagy inhibitor) reversed the regulation of inflammatory cytokines by PGRN. In addition, our study demonstrated that PGRN also enhanced phagocytosis in RAW 264.7 cells. In summary, PGRN attenuated the inflammatory response of A. fumigatus keratitis by increasing autophagy and enhanced the phagocytic activity of RAW 264.7 cells. This showed that PGRN had a protective effect on A. fumigatus keratitis.

First case of fungal keratitis secondary to Yamadazyma mexicana.

First case of fungal keratitis secondary to Yamadazyma mexicana.

Antimicrobial and Immunostimulatory Effects of Senna occidentalis Ethanolic Extract against Aspergillus flavus-Induced Mycotic Keratitis: A Promising Therapeutic Approach

Antimicrobial and Immunostimulatory Effects of Senna occidentalis Ethanolic Extract against Aspergillus flavus-Induced Mycotic Keratitis: A Promising Therapeutic Approach

Phenotypic Screening and Antibiogram of Infectious Ulcerative Keratitis Cases in Tripoli Eye Hospital, Libya

Aims: This study to investigate the most prevalent pathogens that cause corneal ulcer in Tripoli-Libya, and to recognize the antibiogram of the isolated pathogens Study Design: This study was a prospective study performed in eye hospital (Zawyet-Aldahmany eye hospital). Place and Duration of Study: It was conducted at the microbiology laboratory of the hospital over a year from December 2018 to January 2020, The overall size of the sample enrolled in this study was 50 inpatients in the admission department, which was taken according to the incidence of the corneal ulceration cases admitted to the hospital. Methodology: The corneal scrapings and swabs were collected and subjected to microbiological examination. Demographic data and risk factors were collected for each patient. The antibiotic susceptibility of the bacterial microorganisms was determined by the Kirby-Bauer disk diffusion method, to identify the most appropriate antibiotic for each bacterial isolate. Results: 60% of the patients were males, the mean age of the patients was 46.5 years, unilateral right eye keratitis was involved in (54%) of cases, trauma was the major risk factor (24%), followed by systemic disease (14%). Concerning the seasonal distribution of the cases between months, our study revealed that summer and winter seasons in Libya (January, July, August, and September) involved most of the cases, and interestingly, fungal keratitis (Aspergillus) was higher in (July, August), which is the summer season in Libya. The culture positive rate was (80%), of which (36%) were bacterial, and (22%) were fungal pathogens, and the other (22%) were mixed fungal and bacterial cultures. The most common bacterial isolate was (26%) P.aeruginosa and (16%) staphylococcus aureus, while Aspergillus (40%) was the most common fungal isolate, followed by Penicillium and fusarium species. Our results showed that P.aeruginosa was the responsible microorganism for rapid keratitis progression in three cases who were using cosmetic lenses promptly. Concerning antibiotic sensitivity, all gram-negative bacteria and positive isolates were susceptible to old-generation fluoroquinolones such as ciprofloxacin and levofloxacin, while ceftazidime showed resistance to penicillins. Conclusion: In conclusion, with early suspicion and microbiological diagnostic procedures, appropriate therapy can only reduce the incidence of this threatening ocular case.

Involvement of cGAS/STING Signaling in the Pathogenesis of Candida albicans Keratitis: Insights From Genetic and Pharmacological Approaches.

Fungal keratitis (FK) is an invasive corneal infection associated with significant risk to vision. Although the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway has been recognized for its role in defending against viral infections, its involvement in FK still remains largely unclear. This study sought to elucidate the contribution of the cGAS/STING signaling pathway to the pathogenesis of FK. The expression of cGAS/STING signaling components was assessed in a murine model of Candida albicans keratitis through RNA sequencing, western blot analysis, immunofluorescence staining, and real-time PCR. Both genetic (utilizing Sting1gt/gt mice) and pharmacological (using C176) interventions were employed to inhibit STING activity, allowing for the evaluation of resultant pathogenic alterations in FK using slit-lamp examination, clinical scoring, hematoxylin and eosin (H&E) staining, fungal culture, and RNA sequencing. Subconjunctival administration of the NOD-like receptor protein 3 (NLRP3) inflammasome inhibitor MCC950 was performed to evaluate FK manifestations following STING activity blockade. Furthermore, the impact of the STING agonist diABZI on FK progression was investigated. Compared to uninfected corneas, those infected with C. albicans exhibited increased expression of cGAS/STING signaling components, as well as its elevated activity. Inhibiting cGAS/STING signaling exacerbated the advancement of FK, as evidenced by elevated clinical scores, augmented fungal load, and heightened inflammatory response, including NLRP3 inflammasome activation and pyroptosis. Pharmacological inhibition of the NLRP3 inflammasome effectively mitigated the exacerbated FK by suppressing STING activity. Conversely, pre-activation of STING exacerbated FK progression compared to the PBS control, characterized by increased fungal burden and reinforced inflammatory infiltration. This study demonstrates the essential role of the cGAS/STING signaling pathway in FK pathogenesis and highlights the necessity of its proper activation for the host against FK.